Benzamide derivative

ABSTRACT

Compounds having high angiogenesis inhibiting activity useful as agents for effective treatment and prevention of diseases involving pathologic angiogenesis, e.g. cancer and cancer metastasis, are of formula (II), 
                         
where A 1  is C—X 1  or N; Q 1  is -A 2 =A 3 -, or a heteroatom selected from —O—, —S—, and —N(R 10 )—; Q 2  is -A 4 =A 5 -, or a heteroatom selected from —O—, —S—, and —N(R 10 )—; provided that Q 1  and Q 2  are not heteroatoms at the same time; A 2  is C—X 2  or N, A 3  is C—X 3  or N, A 4  is C—X 4  or N, and A 5  is C—X 5  or N; Y is C 1-6 alkyl, C 3-9 cycloalkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 1-6 alkoxy, C 2-7 alkenyloxy, C 2-7 alkynyloxy, or C 1-6 alkylthio; Z is a hydrogen atom, hydroxy, C 1-6 alkyl, C 3-9  cycloalkyl, or —NR 1 R 2 ; and L is selected from the formula:

This is a divisional of allowed application Ser. No. 10/584,233, filedJun. 26, 2006, which is the U.S. National Phase application ofInternational Application No. PCT/JP04/019574 filed Dec. 27, 2004, thecontents of each of which are incorporated herein.

TECHNICAL FIELD

This invention relates to novel benzamide derivatives, pharmaceuticalscontaining them as active ingredients, and particularly, angiogenesisinhibitors useful as agents for treatment of diseases, such as malignanttumors, in which angiogenesis partakes.

BACKGROUND ART

In healthy adults, angiogenesis is only observed as a physiologicalphenomenon, such as endometrial maturation associated with the menstrualcycle, or placentation, and is observed during the process of woundhealing. In pathologic states, however, angiogenesis is noted ininflammation, rheumatoid arthritis, arteriosclerosis, diabeticretinopathy, or solid carcinoma, and may often lead to the progressionor aggravation of these diseases. In solid carcinoma, in particular,cancer tissue grows to a diameter of more than 1 to 2 mm, thusnecessitating the formation of nutrient vessels (see non-patent document1). Furthermore, blood vessels which have infiltrated cancer tissue aredeeply involved in cancer metastasis and the prognosis of cancerpatients (see non-patent document 2 and non-patent document 3).

Thus, an angiogenesis inhibitor is expected as an anticancer drug withminimal injury to normal tissue, unlike an antineoplastic drug showingcytotoxicity, and is also expected as a postoperative adjuvant therapybecause of its effect of suppressing the infiltration and metastasis ofcancer cells.

The process of angiogenesis comprises multiple steps, i.e., destructionof the vascular basement membrane by the dysfunction of vascularendothelial cells forming the lining of the blood vessel, spouting andmigration of vascular endothelial cells, their proliferation, and tubeformation (see non-patent document 4). Vascular endothelial cellsinvolved in angiogenesis are also recruited from vascular endothelialprecursor cells existent in the peripheral blood, etc. (see non-patentdocument 5).

These processes are activated by various angiogenic factors, and manyreports have suggested the relationship between VEGF (vascularendothelial growth factor), which is one of the angiogenic factors, andcancer. In recent years, drugs targeting VEGF, or the tyrosine kinaseactivity of the receptor of VEGF, have been under development (seenon-patent document 6 and non-patent document 7).

Many factors to partake in angiogenesis, other than VEGF, are known. Anearnest demand for the development of inhibitors, which specifically acton vascular endothelial cells playing a central role in angiogenesis andinhibit their proliferation and function, has been uttered, with theexpectation that such inhibitors will be promising as agents fortreatment of angiogenic diseases such as cancer.

There have been no reports so far that benzamide derivatives have aspecific growth inhibitor action on vascular endothelial cells.

As compounds similar in chemical structure to the benzamide derivativesof the present invention, or their salts, those described in thefollowing documents are named:

-   -   Japanese Patent Application Laid-Open No. 2001-526255 (patent        document 1, Warner Lambert),    -   Japanese Patent Application Laid-Open No. 2002-249473 (patent        document 2, Ishihara Sangyo Kaisha),    -   International Publication No. 02/47679 pamphlet (patent document        3, Emory Univ.),    -   International Publication No. 02/059080 pamphlet (patent        document 4, Guilford Pharmaceuticals), and    -   International Publication No. 93/23357 pamphlet (patent document        5, Res. Corporation Tech. Inc.).        However, none of the compounds disclosed in these documents are        described or suggested as having an angiogenesis suppressing        effect. International Publication No. 02/49632 pamphlet (patent        document 6, Institute of Medicinal Molecular Design) discloses        compounds, which are similar in chemical structure to the        benzamide derivatives of the present invention or their salts,        as NFkB activity inhibitors, concretely as IKK inhibitors, and        suggests cancer, cancer metastasis, and vascular hyperplastic        disease as applications for which such inhibitors are targeted.        However, this document does not disclose concrete facts.

KDR tyrosine kinase inhibitors are named as compounds which actspecifically on vascular endothelial cells and inhibit theirproliferation (see non-patent document 8, non-patent document 9, andnon-patent document 10 for outlines). Of these compounds, SU11248(Sugen/Pfizer, a compound having a3-(pyrrol-2-ylmethylidene)-2-indolinone skeleton, see patent document7), PTK787 (Novartis, a compound having a1-anilino-(4-pyridylmethyl)-phthalazine skeleton, see patent document8), ZD6474 (AstraZeneca, a compound having a quinazoline skeleton, seepatent document 9), and CP-547.632 (Pfizer, a compound having anisothiazole skeleton, see patent document 10), for example, are at thestage of clinical development as anticancer drugs. However, all of thesecompounds are different from the present invention in chemical structureand the mechanism of action.

-   -   [Patent document 1] Japanese Patent Application Laid-Open No.        2001-526255    -   [Patent document 2] Japanese Patent Application Laid-Open No.        2002-249473    -   [Patent document 3] International Publication No. 02/47679        pamphlet    -   [Patent document 4] International Publication No. 02/59080        pamphlet    -   [Patent document 5] International Publication No. 93/23357        pamphlet    -   [Patent document 6] International Publication No. 02/49632        pamphlet    -   [Patent document 7] International Publication No. 01/37820        pamphlet    -   [Patent document 8] U.S. Pat. No. 6,258,812    -   [Patent document 9] International Publication No. 01/32651        pamphlet    -   [Patent document 10] International Publication No. 99/62890        pamphlet    -   [Non-patent document 1] Folkmann, J., J. Natul. Cancer Inst.,        Vol. 82, pages 4-6, 1990    -   [Non-patent document 2] Weidner, N. et al. N. Engl. J. Med.,        Vol. 324, pages 1-8, 1991    -   [Non-patent document 3] Bochner, B. H. et al., J. Natl. Cancer        Inst., Vol. 87, pages 1603-1612, 1995    -   [Non-patent document 4] Klagsbrun, M. and Folkmann, J., Handbook        of Experimental Pharmacology, Vol. 95 II, pp. 549-586, 1990    -   [Non-patent document 5] Asahara, T. et al., Science, Vol. 275,        pp. 964-967, 1997    -   [Non-patent document 6] Kabbinavar, F. et al., J. Clinical        Oncology, Vol. 21, pp. 60-65, 2003    -   [Non-patent document 7] Laird, A. D. and Cherrington, J. M.,        Expert Opinion Investigational Drugs, Vol. 12, pp. 51-64, 2003    -   [Non-patent document 8] Boyer, S. J., Current Topics in        Medicinal Chemistry, Vol. 2, pp. 973-1000, 2002    -   [Non-patent document 9] Glade-Bender, J., Kandel, J. J. and        Yamashiro, D. J., Expert Opinion on Biological Therapy, Vol. 3,        No. 2, pp. 263-276, 2003    -   [Non-patent document 10] Laird, A. D. and J. M. Cherrington,        Expert Opinion Investigational Drugs, Vol. 12, No. 1, pp. 51-64,        2003

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide compounds which showstrong anti-angiogenic activity and are useful as agents for treatmentand prevention of diseases involving pathologic angiogenesis, forexample, cancer and cancer metastasis, processes for producing thecompounds, intermediate compounds useful for their production, andpharmaceutical compositions containing these compounds.

Means for Solving the Problems

The inventors diligently conducted studies with the aim of providingnovel agents for treatment and prevention which are effective againstdiseases involving pathologic angiogenesis, for example, cancer andcancer metastasis. As a result, the inventor has found that thecompounds of the present invention have selective and strong activity ofinhibiting angiogenesis. Further, the inventors have discoveredmanufacturing methods capable of easily synthesizing these compounds,and have accomplished the present invention.

According to an aspect of the present invention, there is provided acompound of formula (II), or a prodrug thereof, or a pharmaceuticallyacceptable salt of the compound or the prodrug:

-   -   where A₁ is C—X₁ or N;    -   Q₁ is -A₂=A₃-, or a heteroatom selected from —O—, —S—, and        —N(R_(n))—; Q₂ is -A₄=A₅-, or a heteroatom selected from —O—,        —S—, and —N(R₁₀)—; provided that Q₁ and Q₂ are not heteroatoms        at the same time;    -   A₂ is C—X₂ or N, A₃ is C—X₃ or N, A₄ is C—X₄ or N, and A₅ is        C—X₅ or N;

R₁₀ is a hydrogen atom, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkylcarbonyl oraryl; the aryl being optionally substituted by one or more substituentsselected from a halogen atom, C₁₋₆alkyl, and C₁₋₆alkoxy;

-   -   X₁, X₂, X₃, X₄ and X₅ are each independently selected from the        group consisting of a hydrogen atom, hydroxy, a halogen atom,        cyano, hydroxyaminocarbonyl, hydroxyamidino, nitro, amino,        amidino, guanidino, C₁₋₆alkylamino, diC₁₋₆alkylamino,        C₁₋₆alkylamidino, diC₁₋₆alkylamidino, C₁₋₆alkylguanidino,        diC₁₋₆alkylguanidino, C₁₋₆alkylthio, C₁₋₆alkylsulfo,        C₁₋₆alkylsulfonyl, C₁₋₆alkylphosphono, diC₁₋₆alkylphosphono,        C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₉cycloalkyl, C₃₋₉cycloalkoxy,        C₂₋₇alkenyl, C₂₋₇alkynyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl        (the above 19 groups may be substituted by one or more        substituents selected from a halogen atom, hydroxy, aryl,        heteroaryl, and cyano), aryl, aryloxy, arylcarbonyl, heteroaryl,        heteroaryloxy, heteroarylcarbonyl, and arylC₁₋₆alkyloxy (the        above 7 groups may be substituted by one or more substituents        selected from a halogen atom, C₁₋₆alkyl, and C₁₋₆alkoxy); or

X₁ and X₂, X₂ and X₃, X₃ and X₄, and X₄ and X₅, together with the carbonatoms to which they are bound, form a saturated or unsaturated 5- to7-membered carbocyclic ring, or a saturated or unsaturated 5- to7-membered heterocyclic ring containing one or more heteroatoms selectedfrom an oxygen atom, a nitrogen atom, and a sulfur atom;

Y is selected from the group consisting of C₁₋₆alkyl, C₃₋₉cycloalkyl,C₂₋₇alkenyl, C₂₋₇alkynyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, C₁₋₆alkoxy, C₂₋₇alkenyloxy, C₂₋₇alkynyloxy,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl {the above 15 groups may be substitutedby one or more substituents selected from a saturated or unsaturated 3-to 7-membered carbocyclyl, a saturated or unsaturated 3- to 7-memberedheterocyclyl containing one or more heteroatoms selected from an oxygenatom, a nitrogen atom, and a sulfur atom, a halogen atom, hydroxy,C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy,N—C₁₋₆alkylaminoC₁₋₆alkoxy, N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino,C₁₋₆alkylamino, hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, diC₁₋₆alkylamino, bis(hydroxyC₁₋₆alkyl)amino,bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆alkyl)amino, amidino,C₁₋₆alkylamidino, diC₁₋₆alkylamidino, guanidino, C₁₋₆alkylguanidino,diC₁₋₆alkylguanidino, cyano, carboxyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkylphosphono, anddiC₁₋₆alkylphosphono}, amino, C₁₋₆alkylamino, diC₁₋₆alkylamino (theabove 2 groups may be substituted by one or more substituents selectedfrom a saturated or unsaturated 3- to 7-membered carbocyclyl, asaturated or unsaturated 3- to 7-membered heterocyclyl containing one ormore heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom, a halogen atom, hydroxy, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy, N—C₁₋₆alkylaminoC₁₋₆ alkoxy,N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino, C₁₋₆alkylamino,hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino, aminoC₁₋₆ alkylamino,diC₁₋₆alkylamino, bis(hydroxyC₁₋₆alkyl)amino,bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆alkyl)amino, amidino,C₁₋₆alkylamidino, diC₁₋₆alkylamidino, guanidino, C₁₋₆alkylguanidino,diC₁₋₆alkylguanidino, cyano, carboxyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkylphosphono, anddiC₁₋₆alkylphosphono), a halogen atom, nitro, cyano, carboxyl, and asaturated or unsaturated 3- to 7-membered heterocyclyl containing one ormore heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom (the heterocyclyl may be substituted by one or moresubstituents selected from hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, and oxo); Z is selected from thegroup consisting of a hydrogen atom, hydroxy, C₁₋₆alkyl, C₃₋₉cycloalkyl{the above 2 groups may be substituted by one or more substituentsselected from a saturated or unsaturated 3- to 7-membered carbocyclyl(the carbocyclyl group may be substituted by one or more substituentsselected from C₁₋₆alkyl, hydroxyC₁₋₆alkyl, and C₁₋₆alkoxyC₁₋₆alkyl), asaturated or unsaturated 3- to 7-membered heterocyclyl containing one ormore heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom (the heterocyclyl group may be substituted by one or moresubstituents selected from C₁₋₆alkyl, hydroxyC₁₋₆alkyl, andC₁₋₆alkoxyC₁₋₆alkyl), a halogen atom, hydroxy, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, hydroxyC₁₋₆alkoxyC₁₋₆ alkoxy,aminoC₁₋₆alkoxy, N—C₁₋₆alkylaminoC₁₋₆alkoxy, N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino, C₁₋₆alkylamino, hydroxyC₁₋₆ alkylamino,C₁₋₆alkoxyC₁₋₆alkylamino, aminoC₁₋₆alkylamino, diC₁₋₆alkylamino,bis(hydroxyC₁₋₆alkyl)amino, bis(C₁₋₆alkoxyC₁₋₆ alkyl)amino,bis(aminoC₁₋₆alkyl)amino, cyano, carboxyl, C₁₋₆ alkoxycarbonyl,aryloxycarbonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, diC₁₋₆alkylcarbamoyl{the above 2 groups may be substituted by one or more substituentsselected from a halogen atom, hydroxy, cyano and amino), phosphono, C₁₋₆alkylphosphono, diC₁₋₆alkylphosphono, sulfonic acid, and C₁₋₆alkylsulfo}, and —OR₁ and —NR₁R₂;

-   -   R₁ and R₂ are each dependently selected from the group        consisting of a hydrogen atom, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, and        a saturated or unsaturated 3- to 7-membered heterocyclyl        containing one or more heteroatoms selected from an oxygen atom,        a nitrogen atom, and a sulfur atom (the above 3 groups may be        substituted by one or more substituents selected from a        saturated or unsaturated 3- to 7-membered carbocyclyl, a        saturated or unsaturated 3- to 7-membered heterocyclyl        containing one or more heteroatoms selected from an oxygen atom,        a nitrogen atom, and a sulfur atom, a halogen atom, hydroxy,        C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy,        aminoC₁₋₆alkoxy, N—C₁₋₆alkylaminoC₁₋₆ alkoxy,        N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino, C₁₋₆alkylamino,        hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino, aminoC₁₋₆        alkylamino, diC₁₋₆alkylamino, bis(hydroxyC₁₋₆alkyl)amino,        bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆alkyl)amino, cyano,        carboxyl, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, phosphono,        C₁₋₆alkylphosphono, diC₁₋₆alkylphosphono, sulfonic acid, and        C₁₋₆alkylsulfo); or R₁ and R₂, together with the nitrogen atoms        to which they are bound, form a saturated or unsaturated 5- to        7-membered heterocyclic ring containing one nitrogen atom and        optionally further containing one or more heteroatoms selected        from a oxygen atom, a nitrogen atom, and a sulfur atom; and    -   L is selected from the formula:

In the formula (II), if Q₁ is -A₂=A₃-, A₂ binds to A₁ to form A₁-A₂=A₃-.If Q₂ is -A₄=A₅-, A₄ binds to Q₁ to form Q₁-A₄=A₅-.

Further, if L is —NHC(═O)—, the carbon atom of the carbonyl group bindsto the benzene ring, while the nitrogen atom binds to the followingmoiety:

According to another aspect of the present invention, there is providedthe compound of the formula (II), or the prodrug thereof, or thepharmaceutically acceptable salt of the compound or the prodrug, thecompound being represented by the formula (I):

where A₁, A₂, A₃, A₄, A₅, L, Y, and Z are as defined above.

According to still another aspect of the present invention, there isprovided the compound of the formula (II) or (I), or the prodrugthereof, or the pharmaceutically acceptable salt of the compound or theprodrug, wherein Z is a hydrogen atom, C₁₋₆alkyl, C₃₋₉cycloalkyl,hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxyC₁₋₆ alkyl, C₁₋₆alkoxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, pyridylC₁₋₆alkyl, dihydroxyC₁₋₆alkyl,trihydroxyC₁₋₆alkyl, morpholinoC₁₋₆alkyl, (N,N-diC₁₋₆alkylamino)C₁₋₆alkyl, or (N,N-bis(hydroxyC₁₋₆alkyl) amino) C₁₋₆ alkyl. Examples ofZ in these formulas include a hydrogen atom, methyl, ethyl, cyclopropyl,cyclopentyl, 2-hydroxyethyl, 2-(2-hydroxyethoxy)ethyl, 2-methoxyethyl,2-cyanoethyl, 4-pyridylmethyl, 1-methoxybut-2-yl,2,3-dihydroxyprop-1-yl, 1,3-dihydroxyprop-2-yl,1,3-dihydroxy-2-hydroxymethylprop-2-yl, 2-morpholinoethyl,1-hydroxyprop-2-yl, 1-hydroxy-3-methylbut-2-yl,2-(N,N-dimethylamino)ethyl, 2-(N,N-bis(2-hydroxyethyl)amino)ethyl,2,4-dihydroxylbutyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl,and 2,3,4,5,6-pentahydroxyhexyl.

According to a further aspect of the present invention, there isprovided the compound of the formula (II) or (I), or the prodrugthereof, or the pharmaceutically acceptable salt of the compound or theprodrug, wherein Y is a halogen atom, cyano, C₁₋₆ alkyl, haloC₁₋₆alkyl,C₂₋₇alkenyl, C₂₋₇alkynyl, C₁₋₆alkoxy, C₃₋₉cycloalkylC₁₋₆alkoxy,C₂₋₇alkynyloxy, or haloC₁₋₆alkoxy. Examples of Y in these formulasinclude chloro, bromo, cyano, methyl, trifluoromethyl, ethyl, n-propyl,i-propyl, ethynyl, methoxy, trifluoromethoxy, cyclopropylmethoxy,2-butyn-1-yloxy, and 2-chloroethoxy.

According to a still further aspect of the present invention, there isprovided the compound of the formula (II) or (I), or the prodrugthereof, or the pharmaceutically acceptable salt of the compound or theprodrug, wherein

A₁ is C—X₁ or N, A₂ is C—X₂ or N, A₃ is C—X₃ or N, A₄ is C—X₄ or N, andA₅ is C—X₅ or N;

-   -   X₁, X₂, X₃, X₄ and X₅ are each independently selected from a        hydrogen atom, a halogen atom, C₁₋₆alkyl, C₁₋₆alkoxy,        haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₁₋₆alkylthio, and        haloC₁₋₆alkylthio; or    -   X₁ and X₂, X₂ and X₃, X₃ and X₄, and X₄ and X₅, together with        the carbon atoms to which they are bound, form a cyclohexane        ring, a cyclopentane ring, a benzene ring, a pyridine ring, a        pyrimidine ring, a 1,4-dioxane ring, a 1,3-dioxolane ring, a        pyrrole ring, an imidazole ring, a thiazole ring, or a furan        ring. Examples of X₁, X₂, X₃, X₄ and X₅ in these formulas        include a hydrogen atom, fluoro, chloro, bromo, methyl, ethyl,        t-butyl, i-propyl, methoxy, i-propoxy, trifluoromethyl,        trifluoromethoxy, methylthio, and trifluoromethylthio.        Alternatively, X₁ and X₂, together with the carbon atoms to        which they are bound, form a cyclohexane ring; X₁ and X₂,        together with the carbon atoms to which they are bound, form a        pyridine ring; X₂ and X₃, together with the carbon atoms to        which they are bound, form a 1,4-dioxane ring; or X₂ and X₃,        together with the carbon atoms to which they are bound, form a        cyclopentane ring.

According to an additional aspect of the present invention, there isprovided the compound of the aforementioned formulas, or the prodrugthereof, or the pharmaceutically acceptable salt of the compound or theprodrug, wherein A₁ is C—X₁ or N, A₂ is C—X₂ or N, A₃ is C—X₃ or N, A₄is C—X₄, and A₅ is C—X₅; and two or more of A₁, A₂ and A₃ are not N atthe same time.

According to a still additional aspect of the present invention, thereare provided a pharmaceutical composition, an angiogenesis inhibitor, anagent for treatment and prevention of a disease involving angiogenesis,such as a cancerous disease including solid tumor, and an agent fortreatment and prevention of metastasis of solid tumor, each of thepharmaceutical composition, the angiogenesis inhibitor, and the twoagents containing the above-described compound, or the prodrug thereof,or the pharmaceutically acceptable salt of the compound or the prodrug,as an active ingredient.

In the present invention, the “halogen atom” refers to a fluorine atom,a chlorine atom, a bromine atom, or an iodine atom. If the halogen atomis the substituent for the aromatic carbon ring or the aromaticheterocycle in the present invention, a chlorine atom and a bromine atomare named as examples of the preferred halogen atom. If the halogen atomis the substituent for the alkyl group, or the group containing alkyl inits part (i.e., alkoxy, alkenyl, unsaturated carbon ring, or unsaturatedheterocycle) in the present invention, a fluorine atom is named as anexample of the preferred halogen atom.

In the present invention, the “C₁₋₆alkyl” refers to a straight chain orbranched chain alkyl group having 1 to 6 carbon atoms, including, forexample, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl,t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl,1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl.

In the present invention, the “C₃₋₉cycloalkyl” refers to a cyclic orpartially cyclic alkyl group having 3 to 9 carbon atoms, including, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclopropylmethyl, cyclohexylmethyl, cyclopropylsubstituted by a C₁₋₆alkyl group, cyclopentyl substituted by a C₁₋₄alkylgroup, and cyclohexyl substituted by a C₁₋₃alkyl group.

In the present invention, the “C₂₋₇alkenyl” refers to a straight chainor branched chain alkenyl group having 2 to 7 carbon atoms, including,for example, ethenyl(vinyl), 1-propenyl, 2-propenyl(allyl), propen-2-yl,and 3-butenyl(homoallyl).

In the present invention, the “C₂₋₇alkynyl” refers to a straight chainor branched chain alkynyl group having 2 to 7 carbon atoms, including,for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and3-butynyl.

In the present invention, the “C₁₋₆alkoxy” refers to an alkyloxy grouphaving the straight chain or branched chain alkyl group having 1 to 6carbon atoms which has already been defined as the alkyl portion,including, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy,1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy,3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, and2-ethylbutoxy.

In the present invention, the “aryl” refers to a C₆₋₁₀ aromatichydrocarbon group, including, for example, phenyl, 1-naphthyl, and2-naphthyl.

In the present invention, the “heteroaryl” refers to a 5- to 10-memberedaromatic heterocyclic group containing one or more heteroatoms selectedfrom an oxygen atom, a nitrogen atom and a sulfur atom, including, forexample, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,indolyl, and quinolinyl.

In the present invention, the “C₁₋₆alkylcarbonyl” refers to analkylcarbonyl group having the straight chain or branched chain alkylgroup having 1 to 6 carbon atoms which has already been defined as thealkyl portion, including, for example, acetyl, propionyl,methylpropionyl, and pivaloyl.

In the present invention, the “C₁₋₆alkoxycarbonyl” refers to analkylcarbonyl group having the straight chain or branched chain alkylgroup having 1 to 6 carbon atoms which has already been defined as thealkoxy portion, including, for example, methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl,s-butoxycarbonyl, i-butoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl,3-methylbutoxycarbonyl, 2-methylbutoxycarbonyl, 1-methylbutoxycarbonyl,1-ethylpropoxycarbonyl, n-hexyloxycarbonyl, 4-methylpentoxycarbonyl,3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl,1-methylpentoxycarbonyl, 3-ethylbutoxycarbonyl, and2-ethylbutoxycarbonyl.

In the present invention, the “C₁₋₆alkylthio” refers to an alkylthiogroup having the straight chain or branched chain alkyl group having 1to 6 carbon atoms which has already been defined as the alkyl portion,including, for example, methylthio, ethylthio, n-propylthio,i-propylthio, n-butylthio, s-butylthio, i-butylthio, t-butylthio,n-pentylthio, 3-methylbutylthio, 2-methylbutylthio, 1-methylbutylthio,1-ethylpropylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio,2-methylpentylthio, 1-methylpentylthio, 3-ethylbutylthio, and2-ethylbutylthio.

In the present invention, the “C₁₋₆alkylsulfonyl” refers to analkylsulfonyl group having the straight chain or branched chain alkylgroup having 1 to 6 carbon atoms which has already been defined as thealkyl portion, including, for example, methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, i-propylsulfonyl, n-butylsulfonyl, s-butylsulfonyl,i-butylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl,3-methylbutylsulfonyl, 2-methylbutylsulfonyl, 1-methylbutylsulfonyl,1-ethylpropylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl,3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methylpentylsulfonyl,3-ethylbutylsulfonyl, and 2-ethylbutylsulfonyl.

In the present invention, the “C₁₋₆alkylamino” refers to an alkylaminogroup having the straight chain or branched chain alkyl group having 1to 6 carbon atoms which has already been defined as the alkyl portion,including, for example, methylamino, ethylamino, n-propylamino,i-propylamino, n-butylamino, s-butylamino, i-butylamino, t-butylamino,n-pentylamino, 3-methylbutylamino, 2-methylbutylamino,1-methylbutylamino, 1-ethylpropylamino, n-hexylamino,4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino,1-methylpentylamino, 3-ethylbutylamino, and 2-ethylbutylamino.

In the present invention, the “diC₁₋₆alkylamino” refers to adialkylamino group having two of the straight chain or branched chainalkyl groups having 1 to 6 carbon atoms which have already been definedas the alkyl portions, and these two alkyl portions may be the same ordifferent. The “diC₁₋₆alkylamino” includes, for example, dimethylamino,diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino,methyl-n-butylamino, methyl-s-butylamino, methyl-i-butylamino,methyl-t-butylamino, ethyl-n-butylamino, ethyl-s-butylamino,ethyl-i-butylamino, and ethyl-t-butylamino.

In the present invention, the “saturated or unsaturated 3- to 7-memberedcarbocyclic ring” refers to a saturated, or an unsaturatedbond-containing hydrocarbon ring having 3 to 7 carbon atoms contained inthe ring, and also includes an aromatic hydrocarbon ring. The “saturatedor unsaturated 3- to 7-membered carbocyclic ring” includes, for example,cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclopentene, cyclohexene, and benzene.

In the present invention, the “saturated or unsaturated 5- to 7-memberedcarbocyclic ring” refers to a saturated, or an unsaturatedbond-containing hydrocarbon ring having 5 to 7 carbon atoms contained inthe ring, and also includes an aromatic hydrocarbon ring. The “saturatedor unsaturated 5- to 7-membered carbocyclic ring” includes, for example,cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, andbenzene.

In the present invention, the “saturated or unsaturated 3- to 7-memberedheterocyclic ring” refers to a saturated, or an unsaturatedbond-containing heterocycle, which has 3 to 7 carbon atoms contained inthe ring and contains one or more heteroatoms selected from an oxygenatom, a nitrogen atom and a sulfur atom, and also includes an aromaticheterocycle. The “saturated or unsaturated 3- to 7-membered heterocyclicring” includes, for example, oxirane, aziridine, azetidine, pyrrolidine,piperidine, piperazine, furan, thiophene, pyrrole, imidazole, pyrazole,oxazole, thiazole, thiadiazole, triazole, tetrazole, pyridine,pyrimidine, pyrazine, tetrahydrofuran, tetrahydropyran, 1,4-dioxane,morpholine, and thiomorpholine.

If, in the present invention, the “saturated or unsaturated 3- to7-membered heterocyclyl” binds, as a substituent, to an aromatic carbonring such as a benzene ring, the heterocyclyl includes a saturated orunsaturated 5- to 7-membered heterocyclyl binding to the aromatic carbonring at the nitrogen atom in the ring. The “saturated or unsaturated 3-to 7-membered heterocyclyl” includes, for example, pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl,pyrrol-1-yl, pyrazol-1-yl, and imidazol-1-yl. The preferred heterocyclesare pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, and piperazin-1-yl.

In the present invention, the “saturated or unsaturated 5- to 7-memberedheterocyclic ring” refers to a saturated, or an unsaturatedbond-containing heterocycle, which has 5 to 7 carbon atoms contained inthe ring and contains one or more heteroatoms selected from an oxygenatom, a nitrogen atom and a sulfur atom, and also includes an aromaticheterocycle. The “saturated or unsaturated 5- to 7-memberedheterocyclyl” includes, for example, pyrrolidine, piperidine,piperazine, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole,isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole,tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydrofuran,tetrahydropyran, 1,4-dioxane, morpholine, and thiomorpholine.

In the present invention, the “C₂₋₇alkenyloxy” refers to an alkenyloxygroup having the straight chain or branched chain alkenyl group having 2to 7 carbon atoms which has already been defined as the alkenyl portion.

In the present invention, the “C₂₋₇alkynyloxy” refers to an alkynyloxygroup having the straight chain or branched chain alkynyl group having 2to 7 carbon atoms which has already been defined as the alkynyl portion.

In the present invention, the alkyl portion, the alkynyl portion, andthe alkoxy portion contained in the “C₁₋₆ alkylcarbamoyl”, the“diC₁₋₆alkylcarbamoyl”, the “hydroxyC₁₋₆ alkoxy”, the“C₁₋₆alkoxyC₁₋₆alkoxy”, the “aminoC₁₋₆alkoxy”, the“N—C₁₋₆alkylaminoC₁₋₆alkoxy”, the “N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy”, the“hydroxyC₁₋₆alkylamino”, the “C₁₋₆alkoxyC₁₋₆alkylamino”, the“aminoC₁₋₆alkylamino”, the “bis(hydroxyC₁₋₆alkyl)amino”, the“bis(C₁₋₆alkoxyC₁₋₆alkyl)amino”, the “bis(aminoC₁₋₆alkyl)amino”, the“C₁₋₆alkylamidino”, the “diC₁₋₆alkylamidino”, the “cyanoC₁₋₆alkyl”, the“pyridylC₁₋₆alkyl”, the “C₁₋₆alkoxyC₂₋₇alkyl”, the “hydroxyC₁₋₆ alkyl”,the “hydroxyC₁₋₆alkoxyC₁₋₆alkyl”, the “dihydroxyC₁₋₆alkyl”, the“trihydroxyC₁₋₆alkyl”, the “morpholinoC₁₋₆alkyl”, the“(N,N-diC₁₋₆alkylamino)C₁₋₆alkyl”, or the “(N,N-bis(hydroxyC₁₋₆alkyl)amino)C₁₋₆alkyl” refer to the alkyl group having 1 to 6 carbonatoms, the alkoxy group having 1 to 6 carbon atoms, and the alkynylgroup having 2 to 7 carbon atoms which have already been defined.

In the present invention, no limitation is imposed on the substitutionposition of the alkyl group on the pyridine ring or the morpholine ringin the “pyridylC₁₋₆alkyl” and the “morpholinoC₁₋₆alkyl”.

In the present invention, the “haloC₁₋₆alkyl” refers to an alkyl groupformed by substituting a halogen atom for the straight chain or branchedchain alkyl group having 1 to 6 carbon atoms which has already beendefined as the alkyl portion, the halogen atom being as already defined.The number of the halogen atoms that the haloC₁₋₆alkyl has assubstituents may be 1 or more, and the haloC₁₋₆alkyl includes, forexample, monohaloC₁₋₆alkyl, dihaloC₁₋₆alkyl, trihaloC₁₋₆alkyl, andperhaloC₁₋₆alkyl.

In the present invention, the “haloC₁₋₆alkoxy” refers to an alkoxy groupformed by substituting a halogen atom for the straight chain or branchedchain alkoxy group having 1 to 6 carbon atoms which has already beendefined as the alkoxy portion, the halogen atom being as alreadydefined. The number of the halogen atoms that the haloC₁₋₆alkoxy has assubstituents may be 1 or more, and the haloC₁₋₆alkoxy includes, forexample, monohaloC₁₋₆ alkoxy, dihaloC₁₋₆alkoxy, trihaloC₁₋₆alkoxy, andperhaloC₁₋₆alkoxy.

In the present invention, the “haloC₁₋₆alkylthio” refers to an alkylthiogroup formed by substituting a halogen atom for the straight chain orbranched chain alkyl group having 1 to 6 carbon atoms which has alreadybeen defined as the alkyl portion, the halogen atom being as alreadydefined. The number of the halogen atoms that the haloC₁₋₆alkyl has assubstituents may be 1 or more, and the haloC₁₋₆alkylthio includes, forexample, monohaloC₁₋₆alkylthio, dihaloC₁₋₆alkylthio,trihaloC₁₋₆alkylthio, and perhaloC₁₋₆alkylthio.

In the present invention, the “aryloxycarbonyl” refers toaryloxycarbonyl having the already defined C₆₋₁₀aromatic hydrocarbongroup as the aryl portion, and includes, for example, phenoxycarbonyl,1-naphthoxycarbonyl, and 2-naphthoxycarbonyl.

In the present invention, the “C₁₋₆alkylguanidino” refers to a guanidinogroup (—NHC(NH)NH₂) in which one of the three nitrogen atoms containedhas been substituted by a C₁₋₆alkyl group. The “C₁₋₆alkylguanidino”includes, for example, —NHC(NH)NH(C₁₋₆alky).

In the present invention, the “diC₁₋₆alkylguanidino” refers to aguanidino group (—NHC(NH)NH₂) which has been substituted by C₁₋₆alkylgroups at two sites on the nitrogen atom. The “diC₁₋₆alkylguanidino”includes, for example, —NHC(NH)N(C₁₋₆ alky)₂.

In the present invention, the “diC₁₋₆alkylamidino” refers to an amidinogroup (—C(NH)NH₂) which has been substituted by C₁₋₆alkyl groups at twosites on the nitrogen atom. The “diC₁₋₆ alkylamidino” includes, forexample, —C(NH)N(C₁₋₆alky)₂.

In the present invention, the “hydroxyaminocarbonyl” refers to“—C(O)NH—OH”. In the present invention, the “hydroxyamidino” refers to“—C(NH)NH—OH” or its tautomer.

In the present invention, the “phosphono” refers to “—PO(OH)₂”. In thepresent invention, the “C₁₋₆alkylphosphono” refers to“—PO(OH)(O—C₁₋₆alkyl)” having the already defined C₁₋₆ alkyl as thealkyl portion. The “diC₁₋₆alkylphosphono” refers to “—PO(O—C₁₋₆alkyl)₂”having the already defined C₁₋₆alkyls as the two alkyl portions.

In the present invention, the “sulfonic acid” refers to “—SO₂OH”. In thepresent invention, the “C₁₋₆alkylsulfo” refers to “—SO₂O—C₁₋₆alkyl”having the already defined C₁₋₆alkyl as the alkyl portion.

Herein, the “oxo” refers to “═O”. For example, a methylene groupsubstituted by an oxo group forms a carbonyl group “—C(═O)—”.

In the present invention, the “C₁₋₆alkylamino”, the “diC₁₋₆alkylamino”,the “C₁₋₆alkylamidino”, the “diC₁₋₆alkylamidino”, the“C₁₋₆alkylguanidino”, the “diC₁₋₆alkylguanidino”, the “C₁₋₆ alkylthio”,the “C₁₋₆alkylsulfo”, the “C₁₋₆alkylsulfonyl”, the “C₁₋₆alkylphosphono”, the “diC₁₋₆alkylphosphono”, the “C₁₋₆alkyl”, the“C₁₋₆alkoxy”, the “C₃₋₉cycloalkyl”, the “C₃₋₉cycloalkoxy”, the “C₂₋₇alkenyl”, the “C₂₋₇alkynyl”, the “C₁₋₆alkylcarbonyl”, and“C₁₋₆alkoxycarbonyl” may, in some cases, be substituted by one or moresubstituents selected from a halogen atom, hydroxy, aryl, heteroaryl,and cyano. The number of the substituents may be 1 to the largest numberthat can be taken in terms of chemical structure. The number of thesubstituents is, for example, 1 to 5, preferably 1 to 3.

In the present invention, the “aryl”, the “aryloxy”, the “arylcarbonyl”,the “heteroaryl”, the “heteroaryloxy”, and the “heteroarylcarbonyl” may,in some cases, be substituted by one or more halogen atoms, C₁₋₆alkyls,or C₁₋₆alkoxys. The number of the substituents may be 1 to the largestnumber that can be taken in terms of chemical structure. The number ofthe substituents is, for example, 1 to 5, preferably 1 to 3.

In the present invention, the “C₁₋₆alkyl”, the “C₃₋₉ cycloalkyl”, the“C₂₋₇alkenyl”, the “C₂₋₇alkynyl”, the “C₁₋₆ alkylcarbonyl”,“C₁₋₆alkoxycarbonyl”, the “arylcarbonyl”, the “heteroarylcarbonyl”, the“aryloxycarbonyl”, the “heteroaryloxycarbonyl”, the “C₁₋₆alkoxy”, the“C₂₋₇alkenyloxy”, the “C₂₋₇alkynyloxy”, the “C₁₋₆alkylthio”, and the“C₁₋₆ alkylsulfonyl” may, in some cases, be substituted by one or moresubstituents selected from a saturated or unsaturated 3- to 7-memberedcarbocyclyl, a saturated or unsaturated 3- to 7-membered heterocyclylcontaining one or more heteroatoms selected from an oxygen atom, anitrogen atom, and a sulfur atom, a halogen atom, hydroxy, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy,N—C₁₋₆alkylaminoC₁₋₆alkoxy, N, N-diC₁₋₆alkylaminoC₁₋₆ alkoxy, amino,C₁₋₆alkylamino, hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆ alkylamino,aminoC₁₋₆alkylamino, diC₁₋₆alkylamino, bis(hydroxyC₁₋₆ alkyl)amino,bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆ alkyl) amino, amidino,C₁₋₆alkylamidino, diC₁₋₆alkylamidino, guanidino, C₁₋₆alkylguanidino,diC₁₋₆alkylguanidino, cyano, carboxyl, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,C₁₋₆alkylphosphono, and diC₁₋₆alkylphosphono. The number of thesubstituents may be 1 to the largest number that can be taken in termsof chemical structure. The number of the substituents is, for example, 1to 5, preferably 1 to 3.

In the present invention, the “C₁₋₆alkyl” and the “C₃₋₉ cycloalkyl” may,in some cases, be substituted by one or more substituents selected froma saturated or unsaturated 3- to 7-membered carbocyclyl (the carbocyclylgroup may be substituted by one or more substituents selected fromC₁₋₆alkyl, hydroxyC₁₋₆alkyl, and C₁₋₆alkoxyC₁₋₆alkyl), a saturated orunsaturated 3- to 7-membered heterocyclyl containing one or moreheteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfuratom (the heterocyclyl group may be substituted by one or moresubstituents selected from C₁₋₆alkyl, hydroxyC₁₋₆alkyl, andC₁₋₆alkoxyC₁₋₆alkyl), a halogen atom, hydroxy, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆ alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy,N—C₁₋₆alkylaminoC₁₋₆alkoxy, N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino,C₁₋₆alkylamino, hydroxyC₁₋₆ alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, diC₁₋₆ alkylamino, bis(hydroxyC₁₋₆alkyl) amino,bis(C₁₋₆alkoxyC₁₋₆ alkyl)amino, bis(aminoC₁₋₆alkyl)amino, cyano,carboxyl, C₁₋₆ alkoxycarbonyl, aryloxycarbonyl, phosphono,C₁₋₆alkylphosphono, diC₁₋₆alkylphosphono, sulfonic acid, orC₁₋₆alkylsulfonyl. The number of the substituents may be 1 to thelargest number that can be taken in terms of chemical structure. Thenumber of the substituents is, for example, 1 to 5, preferably 1 to 3.

In the present invention, the “C₁₋₆alkyl”, the “C₁₋₆ alkylcarbonyl”, andthe “saturated or unsaturated 3- to 7-membered heterocyclyl containingone or more heteroatoms selected from an oxygen atom, a nitrogen atom,and a sulfur atom” may, in some cases, be substituted by one or moresubstituents selected from a saturated or unsaturated 3- to 7-memberedcarbocyclyl, a saturated or unsaturated 3- to 7-membered heterocyclylcontaining one or more heteroatoms selected from an oxygen atom, anitrogen atom, and a sulfur atom, a halogen atom, hydroxy, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy, N—C₁₋₆alkylaminoC₁₋₆alkoxy, N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino, C₁₋₆alkylamino, hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, diC₁₋₆alkylamino, bis(hydroxyC₁₋₆alkyl)amino,bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆alkyl)amino, cyano,carboxyl, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, phosphono,C₁₋₆alkylphosphono, diC₁₋₆alkylphosphono, sulfonic acid, or C₁₋₆alkylsulfo. The number of the substituents may be 1 to the largestnumber that can be taken in terms of chemical structure. The number ofthe substituents is, for example, 1 to 5, preferably 1 to 3.

Herein, if the arbitrary group is substituted by one or moresubstituents, these substituents may be the same or different, and thenumber of the substituents is 1 to the largest number that cansubstituent in terms of chemical structure. The number of thesubstituents is, for example, 1 to 7, typically 1 to 5, preferably 1 to3.

The Group which the compound of the present invention represented by theformula (II) has, includes, for example, the following aromatic carbonring groups or aromatic heterocyclic groups:

The present invention includes salts of the compounds represented by theformula (I) or the formula (II), and pharmaceutically acceptable saltsof prodrugs of the compounds. These salts are produced by bringing thecompounds or the prodrugs of the compounds into contact with acids orbases which can be used in the production of medicines. These saltsinclude, for example, hydrochlorides, hydrobromides, hydriodides,sulfates, sulfonates, phosphates, phosphonates, carboxylates such asacetates, citrates, malates and salicylates, or alkali metal salts suchas sodium salts and potassium salts; alkaline earth metal salts such asmagnesium salts and calcium salts; and ammonium salts such as ammoniumsalts, alkylammonium salts, dialkylammonium salts, trialkylammoniumsalts, and tetraalkylammonium salts.

The “prodrugs” in the present invention refer to derivatives of thecompounds of the formula (I) or (II) which are converted into thecompounds of the formula (I) or (II) or their pharmaceuticallyacceptable salts by enzymatic or non-enzymatic decomposition underphysiological conditions. The prodrugs are those which may be inert whenadministered to patients, but in vivo, are present in active formsconverted into the compounds of the formula (I) or (II).

The prodrugs are those which may be inert when administered to patients,but in vivo, are present in active forms converted into the compounds ofthe formula (I).

Next, the methods of producing the compounds of the present inventionwill be described. If, in the manufacturing methods shown below, thedefined groups undergo undesirable chemical conversion under theconditions of the methods practiced, the production can be performed byusing means such as protection or deprotection of functional groups.Operations for selecting and detaching the protective groups can beperformed, for example, by the methods described in “Greene and Wuts,“Protective Groups in Organic Synthesis” (2nd Ed., John Wiley & Sons,1991)”. These methods may be employed, as appropriate, according to thereaction conditions. Where necessary, the sequence of the reaction stepssuch as the introduction of substituents can be changed. Various methodare conceivable as the manufacturing methods for the compounds of thepresent invention represented by formula (I), and these compounds can besynthesized by use of ordinary means for organic synthesis.Representative methods which can produce the compounds are as shownbelow.

Representative Methods for Manufacture

Manufacturing Method 1

The compounds of the formula (II) where L denotes —NH—C(O)— can beproduced, for example, by the method shown as the manufacturing method1-1, 1-2, 1-3 or 1-4.

Manufacturing Method 1-1

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection. LG denotes a leavinggroup applicable to the reaction concerned, such as halogen orsulfonate.

Step 1 (Amidation)

An amine derivative (1-1-A) and a benzoic acid derivative (1-1-B) aresubjected to dehydration condensation, whereby an amide (1-1-C) can beprepared. This reaction is carried out under reaction conditions at 0°C. to 180° C. in an aprotic solvent in the presence of an acidhalogenating agent or a dehydration condensation agent, in the presenceor absence of an active esterifying agent, or in the presence or absenceof a base.

Examples of the acid halogenating agent are oxalyl chloride and thionylchloride. Examples of the dehydration condensation agent arecarbodiimide compounds carried on polymers (for example,N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene(PS-carbodiimide), 1,3-dicyclohexylcarbodiimide (DCC),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),bromo-tris(pyrrolidino)-phosphonium=hexafluorophosphate (PyBrOP),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC), and(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate(PyBOP)). Examples of the active esterifying agent areN-hydroxybenzotriazole (HOBt), di(N-succinimidyl)carbonate, andcarbonyldiimidazole. Examples of the base are triethylamine,N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).Examples of the aprotic solvent are carboxylic acid amides such asformamide or N,N-dimethylformamide, halogenated hydrocarbons such asdichloromethane, carbon tetrachloride or chlorobenzene, ketones such asacetone, cyclic ethers such as tetrahydrofuran or dioxane, esters suchas ethyl acetate, nitriles such as acetonitrile, and their mixtures.

Step 2 (Cyanation)

In the formulas, LG denotes a leaving group applicable to the reactionconcerned, such as a halogen atom or sulfonate. Cyanation of a compoundhaving a leaving group on the benzene ring can be performed, forexample, by applying, as appropriate, the method described in SyntheticCommunication, 887-90, 24(6), (1994). Concretely, the compound (1-1-C)is reacted with a metal cyanide, for example, zinc cyanide, in a solventinert to the reaction, for example, N,N-dimethylformamide, in thepresence of a catalytic amount of a palladium complex, for example,tetrakistriphenylphosphine palladium, whereby a corresponding cyanationproduct (1-1-D) can be obtained.

Step 3 (Nitrile Hydrolysis)

The hydrolysis of the nitrile group to an amide can be performed, forexample, by applying, as appropriate, a method using hydrogen peroxideand an inorganic base (for example, Org. Syn. Coll. vol. 2, 586-588(1943), and J. Med. Chem., 43, 873-882 (2000)), a method performed in analiphatic alcohol or dimethy sulfoxide in the presence of an inorganicbase (for example, Japanese Patent Application Laid-Open No. 2000-86610or Japanese Patent Application Laid-Open No. 2001-39936), or a methodinvolving hydrolysis in the presence of an acid (Japanese PatentApplication Laid-Open No. 1994-239810). The preferred method is theconversion of the nitrile group into an amide (1-1-E) performed using anaqueous solution of hydrogen peroxide in the presence of an inorganicbase, for example, potassium carbonate. Dimethyl sulfoxide or the likecan be used as the reaction solvent. The reaction time is about 10minutes to about 30 hours. The reaction temperature is in a temperaturerange of from about 10° C. to about 100° C.

Step 4 (Deprotection, Functional Group Modification)

If the amide (1-1-E) has a protective group and/or a substituent capableof functional group modification (for example, a hydroxyl group, anamino group, halogen, a carboxyl group, a carbonyl group, a nitro group,a cyano group, or carbon-carbon unsaturated bond), a deprotectionreaction and/or functional group modification is performed during thisstep, whereby a compound (1-1-F), the desired final product, can beproduced. Various publicly known methods are available for thisreaction, and selection and detachment of the protective group areperformed, for example, by the method described in “Greene and Wuts,“Protective Groups in Organic Synthesis” (2^(nd) Ed., John Wiley & Sons,1991)”. The functional group modification reaction is performed, forexample, by the method described in “Smith and March, “March's AdvancedOrganic Chemistry” (5^(th) Ed., John Wiley & Sons, 2001)” or “Richard C.Larock, Comprehensive Organic Transformations (VCH Publishers, Inc.1989)”.

Manufacturing Method 1-2

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection. R represents a C₁₋₆ alkylgroup such as methyl, ethyl, propyl, butyl, pentyl, isopropyl, ortert-butyl. In the amidation of step 3, an optically active amine isused as the starting material, whereby the compound of the presentinvention having optical activity can be obtained.

Manufacturing Method 1-3

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection.

Manufacturing Method 1-4

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection.

Step 1 (Amidation 1)

The same conditions as those for the amidation of Step 1 in themanufacturing method 1-1 can be applied.

Step 2 (Nitrile Hydrolysis)

The same conditions as those for the nitrile hydrolysis of Step 3 in themanufacturing method 1-1 can be applied.

Step 3 (Deprotection, Functional Group Modification)

The same conditions as those for the deprotection and functional groupmodification of Step 4 in the manufacturing method 1-1 can be applied.

Manufacturing Method 2

The compounds of the formula (II) where L denotes —CH═CH— can beproduced, for example, by the method shown as the manufacturing method2-1, 2-2, 2-3 or 2-4.

Manufacturing Method 2-1

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection. LG denotes a leavinggroup applicable to the reaction concerned, such as halogen orsulfonate. W represents an O,O′-di-hydrocarbon-phosphono group, or atriarylphosphonium group. If W represents a triarylphosphonium group, apart of the phenyl group of the phosphonium portion may be polymerized.

Manufacturing Method 2-2

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection. R represents a C₁₋₆ alkylgroup such as methyl, ethyl, propyl, butyl, pentyl, isopropyl, ortert-butyl. W represents an O,O′-di-hydrocarbon-phosphono group, or atriarylphosphonium group. If W represents a triarylphosphonium group, apart of the phenyl group of the phosphonium portion may be polymerized.In the amidation of step 3, an optically active amine is used as thestarting material, whereby the compound of the present invention havingoptical activity can be obtained.

Manufacturing Method 2-3

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection. W represents anO,O′-di-hydrocarbon-phosphono group, or a triarylphosphonium group. If Wrepresents a triarylphosphonium group, a part of the phenyl group of thephosphonium portion may be polymerized.

Manufacturing Method 2-4

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection. W represents anO,O′-di-hydrocarbon-phosphono group, or a triarylphosphonium group. If Wrepresents a triarylphosphonium group, a part of the phenyl group of thephosphonium portion may be polymerized.

Manufacturing Method 2-5

In the formulas, A₁, Q₁, Q₂, Y and Z are as defined in the formula (II),and Aa₁, Qa₁, Qa₂, Y₁, and Z₁, respectively, have the same definitionsas for A₁, Q₁, Q₂, Y and Z in the definitions of the formula (II), orrepresent groups which can be converted into A₁, Q₁, Q₂, Y and Z byfunctional group modification or deprotection. W represents anO,O′-di-hydrocarbon-phosphono group, or a triarylphosphonium group. If Wrepresents a triarylphosphonium group, a part of the phenyl group of thephosphonium portion may be polymerized.

Manufacturing Method 3

The compounds of the formula (I) where L denotes —NH—C(O)— can beproduced, for example, by the method shown as the manufacturing method3-1, 3-2 or 3-3.

Manufacturing Method 3-1

In the formulas, X₁, X₂, X₃, X₄, X₅, Y and Z are as defined in theformula (I), and Xa₁, Xa₂, Xa₃, Xa₄, Xa₅, Y₁, and Z₂, respectively, havethe same definitions as for X₁, X₂, X₃, X₄, X₅, Y and Z in thedefinitions of the formula (I), or represent groups which can beconverted into X₁, X₂, X₃, X₄, X₅, Y and Z by functional groupmodification or deprotection. LG denotes a leaving group applicable tothe reaction concerned, such as halogen or sulfonate.

Step 1 (Amidation)

An aniline derivative (3-1-A) and a benzoic acid derivative (3-1-B) aresubjected to dehydration condensation, whereby an amide (3-1-C) can beprepared. This reaction is carried out under reaction conditions at 0°C. to 180° C. in an aprotic solvent in the presence of an acidhalogenating agent or a dehydration condensation agent, in the presenceor absence of an active esterifying agent, or in the presence or absenceof a base.

Examples of the acid halogenating agent are oxalyl chloride and thionylchloride. Examples of the dehydration condensation agent arecarbodiimide compounds carried on polymers (for example,N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene(PS-carbodiimide), 1,3-dicyclohexylcarbodiimide (DCC),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC), and(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate(PyBOP)). Examples of the active esterifying agent areN-hydroxybenzotriazole (HOBt), di(N-succinimidyl)carbonate, andcarbonyldiimidazole. Examples of the base are triethylamine,N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).Examples of the aprotic solvent are carboxylic acid amides such asformamide or N,N-dimethylformamide, halogenated hydrocarbons such asdichloromethane, carbon tetrachloride or chlorobenzene, ketones such asacetone, cyclic ethers such as tetrahydrofuran or dioxane, esters suchas ethyl acetate, nitriles such as acetonitrile, and their mixtures.

Step 2 (Cyanation)

In the formulas, LG denotes a leaving group applicable to the reactionconcerned, such as a halogen atom or sulfonate. Cyanation of a compoundhaving a leaving group on the benzene ring can be performed, forexample, by applying, as appropriate, the method described in SyntheticCommunication, 887-90, 24(6), (1994). Concretely, the compound (3-1-C)is reacted with a metal cyanide, for example, zinc cyanide, in a solventinert to the reaction, for example, N,N-dimethylformamide, in thepresence of a catalytic amount of a palladium complex, for example,tetrakistriphenylphosphine palladium, whereby a corresponding cyanationproduct (3-1-D) can be obtained.

Step 3 (Nitrile Hydrolysis)

The hydrolysis of the nitrile group to an amide can be performed, forexample, by applying, as appropriate, a method using hydrogen peroxideand an inorganic base (for example, Org. Syn. Coll. vol. 2, 586-588(1943), and J. Med. Chem., 43, 873-882 (2000)), a method performed in analiphatic alcohol or dimethy sulfoxide in the presence of an inorganicbase (for example, Japanese Patent Application Laid-Open No. 2000-86610or Japanese Patent Application Laid-Open No. 2001-39936), or a methodinvolving hydrolysis in the presence of an acid (Japanese PatentApplication Laid-Open No. 1994-239810). The preferred method is theconversion of the nitrile group into an amide (3-1-E) performed using anaqueous solution of hydrogen peroxide in the presence of an inorganicbase, for example, potassium carbonate. Dimethyl sulfoxide or the likecan be used as the reaction solvent. The reaction time is about 10minutes to about 30 hours. The reaction temperature is in a temperaturerange of from about 10° C. to about 100° C.

Step 4 (Deprotection, Functional Group Modification)

If the amide (3-1-E) has a protective group and/or a substituent capableof functional group modification (for example, a hydroxyl group, anamino group, halogen, a carboxyl group, a carbonyl group, a nitro group,a cyano group, or carbon-carbon unsaturated bond), a deprotectionreaction and/or functional group modification is performed during thisstep, whereby a compound (3-1-F), the desired final product, can beproduced. Various publicly known methods are available for thisreaction, and selection and detachment of the protective group areperformed, for example, by the method described in “Greene and Wuts,“Protective Groups in Organic Synthesis” (2nd Ed., John Wiley & Sons,1991)”. The functional group modification reaction is performed, forexample, by the method described in “Smith and March, “March's AdvancedOrganic Chemistry” (5th Ed., John Wiley & Sons, 2001)” or “Richard C.Larock, Comprehensive Organic Transformations (VCH Publishers, Inc.1989)”.

Manufacturing Method 3-2

In the formulas, X₁, X₂, X₃, X₄, X₅, Y and Z are as defined in theformula (I), and Xa₁, Xa₂, Xa₃, Xa₄, Xa₅, Y₁, and Z₁, respectively, havethe same definitions as for X₁, X₂, X₃, X₄, X₅, Y and Z in thedefinitions of the formula (I), or represent groups which can beconverted into X₁, X₂, X₃, X₄, X₅, Y and Z by functional groupmodification or deprotection. R represents a C₁₋₆ alkyl group such asmethyl, ethyl, propyl, butyl, pentyl, isopropyl, or tert-butyl.

Step 1 (Amidation 1)

The same conditions as those for the amidation of Step 1 in themanufacturing method 3-1 can be applied.

Step 2 (Ester Hydrolysis)

For the hydrolysis of the ester group, there are named, for example, amethod involving hydrolysis performed in an aqueous solvent, forexample, an alcohol-based solvent, in the presence of an inorganic base(for example, Corey, E. J.; Szekely, I.; Shiner, C. S. Tetrahedron Lett.3529, 1977), and a method of hydrolysis in the presence of an acid (forexample, Bryan, D. B.; Hall, R. F.; Holden, K. G.; Fuffman, W. F.;Gleason, J. G. J. Am. Chem. Soc., 1977, 99, 2353). The methods describedthere can be applied, as appropriate, for the hydrolysis. The preferredmethod is the hydrolysis of the ester group performed using an aqueoussolution of potassium hydroxide or sodium hydroxide in an alcoholsolvent such as ethanol. The reaction time is about 10 minutes to about30 hours, preferably about 30 minutes to about 3 hours. The reactiontemperature is in a temperature range of from about 0° C. to the boilingpoint of the solvent, preferably about 80° C. to about 100° C.

Step 3 (Amidation 2)

Various amines, for example, ammonia, hydrazine, mono-substitutedamines, substituted hydrazines, and a benzoic acid derivative (3-2-D)are subjected to dehydration condensation, whereby an amide (3-2-E) canbe prepared. This reaction is carried out under reaction conditions at0° C. to 180° C. in an aprotic solvent in the presence of an acidhalogenating agent or a dehydration condensation agent, in the presenceor absence of an active esterifying agent, or in the presence or absenceof a base. By using an optically active amine as the starting material,the compound of the present invention having optical activity can beobtained.

Examples of the acid halogenating agent are oxalyl chloride and thionylchloride. Examples of the dehydration condensation agent arecarbodiimide compounds carried on polymers (for example,N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene(PS-carbodiimide), 1,3-dicyclohexylcarbodiimide (DCC),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC), and(benzotriazolyloxy)tripyrrolidino-phosphonium=hexafluorophosphate(PyBOP)). Examples of the active esterifying agent areN-hydroxybenzotriazole (HOBt), di(N-succinimidyl)carbonate, andcarbonyldiimidazole. Examples of the base are triethylamine,N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).Examples of the aprotic solvent are carboxylic acid amides such asformamide or N,N-dimethylformamide, halogenated hydrocarbons such asdichloromethane, carbon tetrachloride or chlorobenzene, ketones such asacetone, cyclic ethers such as tetrahydrofuran or dioxane, esters suchas ethyl acetate, nitriles such as acetonitrile, and their mixtures.

Method of Amidation Involving (Step 2+Step 3) Performed in Single Step

The benzoic acid-derived ester derivative (3-2-C) obtained in step 1 canbe converted into the amide (3-2-E) without undergoing the esterhydrolysis of step 2. That is, this reaction is carried out by reactingthe benzoic acid-derived ester derivative with various amines, such asammonia or aliphatic amine, at atmospheric pressure or under pressureunder reaction conditions at 0° C. to 180° C. in an aprotic or protonicsolvent in the presence or absence of an activator such as a Lewis acid.

Step 4 (Deprotection, Functional Group Modification)

The same conditions as those for the deprotection and functional groupmodification of Step 4 in the manufacturing method 3-1 can be applied.

Manufacturing Method 3-3

In the formulas, X₁, X₂, X₃, X₄, X₅, Y and Z are as defined in theformula (I), and Xa₁, Xa₂, Xa₃, Xa₄, Xa₅, Y₁, and Z₂, respectively, havethe same definitions as for X₁, X₂, X₃, X₄, X₅, Y and Z in thedefinitions of the formula (I), or represent groups which can beconverted into X₁, X₂, X₃, X₄, X₅, Y and Z by functional groupmodification or deprotection.

Step 1 (Amidation 1)

The same conditions as those for the amidation of Step 1 in themanufacturing method 3-1 can be applied.

Step 2 (Deprotection, Functional Group Modification)

The same conditions as those for the deprotection and functional groupmodification of Step 4 in the manufacturing method 3-1 can be applied.

Manufacturing Method 4

The compounds of the formula (I) where L denotes —CH═CH— can beproduced, for example, by the method shown as the manufacturing method4-1, 4-2, or 4-3.

Manufacturing Method 4-1

In the formulas, X₁, X₂, X₃, X₄, X₅, Y and Z are as defined in theformula (I), and Xa₁, Xa₂, Xa₃, Xa₄, Xa₅, Y₁, and Z₂, respectively, havethe same definitions as for X₁, X₂, X₃, X₄, X₅, Y and Z in thedefinitions of the formula (I), or represent groups which can beconverted into X₁, X₂, X₃, X₄, X₅, Y and Z by functional groupmodification or deprotection. LG denotes a leaving group applicable tothe reaction concerned, such as halogen or sulfonate. W represents anO,O′-di-hydrocarbon-phosphono group, or a triarylphosphonium group. If Wrepresents a triarylphosphonium group, a part of the phenyl group of thephosphonium portion may be polymerized.

Step 1 (Condensation)

A phosphorus compound (4-1-A) and an aldehyde (4-1-B) are subjected todehydration condensation, whereby the desired stilbene derivative(4-1-C) can be produced. This reaction is performed in a solvent in thepresence of a base at a reaction temperature of −78° C. to the boilingpoint of the solvent. Examples of the base are inorganic bases such assodium carbonate, potassium carbonate, sodium hydride, potassiumhydride, or calcium hydride, and organic bases such as pyridine,triethylamine, N,N-diisopropylethylamine, lithium diisopropylamide,lithium hexamethyldisilazide, n-butyl lithium, and sodium amide.Preferably, sodium hydride, lithium diisopropylamide, or lithiumhexamethyldisilazide can be named. Examples of the solvent arenon-reactive solvents, including tetrahydrofuran, diethyl ether,dioxane, methanol, ethanol, toluene, n-hexane, and dimethylformamide.The preferred examples are tetrahydrofuran, and diethyl ether.

Step 2 (Cyanation)

The same conditions as those for the cyanation of Step 2 in themanufacturing method 3-1 can be applied.

Step 3 (Nitrile Hydrolysis)

The same conditions as those for the nitrile hydrolysis of Step 3 in themanufacturing method 3-1 can be applied.

Step 4 (Deprotection, Functional Group Modification)

The same conditions as those for the deprotection and functional groupmodification of Step 4 in the manufacturing method 3-1 can be applied.

Manufacturing Method 4-2

In the formulas, X₁, X₂, X₃, X₄, X₅, Y and Z are as defined in theformula (I), and Xa₁, Xa₂, Xa₃, Xa₄, Xa₅, Y₁, and Z₂, respectively, havethe same definitions as for X₁, X₂, X₃, X₄, X₅, Y and Z in thedefinitions of the formula (I), or represent groups which can beconverted into X₁, X₂, X₃, X₄, X₅, Y and Z by functional groupmodification or deprotection. R represents a C₁₋₆ alkyl group such asmethyl, ethyl, propyl, butyl, pentyl, isopropyl, or tert-butyl. Wrepresents an O,O′-di-hydrocarbon-phosphono group, or atriarylphosphonium group. If W represents a triarylphosphonium group, apart of the phenyl group of the phosphonium portion may be polymerized.

Step 1 (Condensation)

The same conditions as those for the condensation of Step 1 in themanufacturing method 4-1 can be applied.

Step 2 (Ester Hydrolysis)

The same conditions as those for the ester hydrolysis of Step 2 in themanufacturing method 3-2 can be applied.

Step 3 (Amidation)

The same conditions as those for the amidation 2 of Step 3 in themanufacturing method 3-2 can be applied. By using optically activeamines as starting materials, the compounds of the present invention,which are optically active, can be obtained.

Amidation Method Involving (Step 2+Step 3) Performed in Single Step

The benzoic acid-derived ester derivative obtained in step 1 can beconverted into the amide without undergoing the ester hydrolysis of step2. That is, this reaction is carried out by reacting the benzoicacid-derived ester derivative with various amines, such as ammonia oraliphatic amine, at atmospheric pressure or under pressure underreaction conditions at 0° C. to 180° C. in an aprotic or protonicsolvent in the presence or absence of an activator such as a Lewis acid.

Step 4 (Deprotection, Functional Group Modification)

The same conditions as those for the deprotection and functional groupmodification of Step 4 in the manufacturing method 3-1 can be applied.

Manufacturing Method 4-3

In the formulas, X₁, X₂, X₃, X₄, X₅, Y and Z are as defined in theformula (I), and Xa₁, Xa₂, Xa₃, Xa₄, Xa₅, Y₁, and Z₁, respectively, havethe same definitions as for X₁, X₂, X₃, X₄, X₅, Y and Z in thedefinitions of the formula (I), or represent groups which can beconverted into X₁, X₂, X₃, X₄, X₅, Y and Z by functional groupmodification or deprotection. W represents anO,O′-di-hydrocarbon-phosphono group, or a triarylphosphonium group. If Wrepresents a triarylphosphonium group, a part of the phenyl group of thephosphonium portion may be polymerized.

Step 1 (Condensation)

The same conditions as those for the condensation of Step 1 in themanufacturing method 4-1 can be applied.

Step 2 (Deprotection, Functional Group Modification)

The same conditions as those for the deprotection and functional groupmodification of Step 4 in the manufacturing method 3-1 can be applied.

Synthesis of Starting Compounds

Some of the starting compounds for the compounds of the presentinvention are novel compounds, and these compounds can be synthesizedeasily in the same manner as for the publicly known starting compounds,or by use of methods publicly known to people skilled in the art.

Examples of the amine usable as the starting material in the amidationstep in the manufacturing methods 1-2, 2-2, 3-2 and 4-2 are opticallyactive forms of amines selected from 2,4-dihydroxybutylamine,2,3,4-trihydroxybutylamine, 2,3-dihydroxypropylamine,2-hydroxy-1-methylethylamine and 1-methoxymethylpropylamine, and aminoacids such as serine, homoserine, threonine, tyrosine, lysine, glutamicacid and aspartic acid. When an amino acid is used in the amidationstep, the carboxy group and/or a functional group contained in the aminoacid residue of the amino acid may be protected by a protective group.Further, the compound obtained by the amidation step may be subjected todeprotection and/or functional group modification, for example amidationof the carboxy group. These chemical conversions can be carried out inaccordance with a procedure well known to those skilled in the art or aprocedure as described in Examples hereinafter.

An example of the manufacturing method for the compounds of the formula(I) and the formula (II) according to the present invention has beendescribed above. The isolation and purification of the desired compoundsin the above-described reaction steps can be performed by applyingordinary chemical procedures, such as extraction, concentration, removalby distillation, crystallization, filtration, recrystallization, andvarious chromatographic techniques.

The compounds of the present invention, and their pharmaceuticallyacceptable salts include all stereoisomers (for example, enantiomers anddiastereomers (cis-geometric isomers and trans-geometric isomers)) ofthe compounds represented by the formula (I) and the formula (II),racemic bodies of these isomers, and other mixtures thereof. Forexample, the compounds of the present invention may be those of theformulas (I) and (II) in which Z has one or more asymmetric points. Thepresent invention includes racemic mixtures, diastereomer mixtures, andenantiomers of such compounds.

The compounds of the present invention, and their pharmaceuticallyacceptable salts can be present in several tautomeric forms, forexample, enol and imine forms, keto and enamine forms, and as mixturesthereof. The tautomers exist in solutions as mixtures of tautomericsets. In the solid form, one of the tautomers is usually predominant.One of the tautomers may be described herein, but in the presentinvention, all tautomers of the compounds of the present invention areincluded.

If the compounds according to the present invention are obtained as freecompounds, they can be converted into salts, their hydrates, or theirsolvates, which the compounds may form, in accordance with theconventional methods.

If the compounds according to the present invention are obtained assalts, hydrates, or solvates of the compounds, they can be convertedinto the free forms of the compounds in accordance with the conventionalmethods.

The compounds of the present invention, and their pharmaceuticallyacceptable salts have an excellent angiogenesis inhibiting action, areexcellent in stability in the body and solubility in water, and areuseful as prophylactic or therapeutic agents (especially, therapeuticagents) for proliferative diseases. Also, the compounds of the presentinvention, and their pharmaceutically acceptable salts are useful asprophylactic or therapeutic agents (especially, therapeutic agents) fordiseases, such as various cancers, for example, breast cancer, coloncancer, rectal cancer, ovarian cancer, pulmonary cancer, pancreaticcancer, hepatic cancer, uterine cancer, brain cancer, prostatic cancer,acute leukemia, and gastric cancer. Further, the compounds of thepresent invention are useful as prophylactic or therapeutic agents(especially, therapeutic agents) for the infiltration and metastasis ofsolid cancer. Additionally, the compounds of the present invention areeffective as prophylactic or therapeutic agents for other diseasesrelated to angiogenesis, for example, Alzheimer disease and HIVinfection.

These methods include the step of administering medically effectiveamounts of pharmaceutical compositions containing the compounds of thepresent invention and their pharmaceutically acceptable salts, whichhave been disclosed above, to patients requiring such therapies orsuffering from such diseases or states.

If the pharmaceutical composition of the present invention is used as anangiogenesis inhibitor, or an agent for treatment or prevention ofproliferative disease, the method of its administration includes, forexample, oral, rectal, parenteral (intravenous, intramuscular,subcutaneous), intracisternal, intravaginal, intraperitoneal,intravesical, and local (drip infusion, powder, ointment, gel or cream)administration and inhalation (intraoral or nasal spray). The dosageforms are, for example, tablets, capsules, granules, powders, pills,aqueous and nonaqueous oral solutions and suspensions, and parenteralsolutions charged into containers suitable for dispensing intoindividual doses. The dosage forms can also be adapted for various modesof administration including controlled release prescriptions, such assubcutaneous implantation.

The above-mentioned preparations can be produced by well-known methodsusing additives, such as vehicles, tablet lubricants (coating agents),binders, disintegrants, stabilizers, taste and odor correctives, anddiluents.

Examples of the vehicles are starches such as starch, potato starch, andcorn starch, lactose, microcrystalline cellulose, and calcium hydrogenphosphate.

Examples of the coating agents are ethylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose, shellac, talc,carnauba wax, and paraffin.

Examples of the binders are polyvinylpyrrolidone, macrogol, and the samecompounds as the above-mentioned vehicles.

Examples of the disintegrants are the same compounds as theabove-mentioned vehicles, and chemically modified starch-celluloses suchas croscarmellose sodium, sodium carboxymethylstarch, and crosslinkedpolyvinylpyrrolidone.

Examples of the stabilizers are parahydroxybenzoate esters such asmethylparaben and propylparaben; alcohols such as chlorobutanol, benzylalcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such asphenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

As the taste and odor correctives, there can be named sweeteners, souragents, and flavors which are usually used.

As the solvents for producing liquid and solution preparations, ethanol,phenol, chlorocresol, purified water, and distilled water can be used.

As surfactants and emulsifiers, polysorbate 80, polyoxyl 40 stearate,and lauromacrogol, for example, can be named.

In using the pharmaceutical composition of the present invention as aninhibitor of angiogenesis, or an agent for treatment or prevention ofproliferative disease, the amount of the compound of the presentinvention or its pharmaceutically acceptable salt used differs accordingto symptoms, age, body weight, and relative health condition of thepatient, the presence of other drug administered, and the mode ofadministration. In the patient (warm-blooded animal, especially human),for example, the generally effective dose, as the active ingredient (thecompound of the present invention represented by the formula (I) or theformula (II)), is preferably 0.1 to 1000 mg per kg of body weight perday, more preferably 1 to 300 mg per kg of body weight, in the case ofan oral preparation. The daily dose in an adult patient of normal bodyweight is preferably in the range of 10 to 800 mg. In the case of aparenteral preparation, the dose is preferably 0.1 to 1000 mg per kg ofbody weight per day, more preferably 10 to 800 mg per kg of body weight.This dose is desirably administered once daily or in several portionsdaily according to symptoms.

Effects of the Invention

The present invention provides benzamide compounds having highangiogenesis inhibiting activity which results from the mechanism ofaction different from that of the existing NF-kB inhibitory effect andKDR tyrosine kinase activity inhibition. The present invention alsoprovides compounds which are useful as agents for treatment andprevention of diseases involving pathologic angiogenesis, for example,cancer and cancer metastasis, methods for producing the compounds,intermediate compounds useful for their production, and pharmaceuticalcompositions containing these compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 An example of the results of antitumor test, showing changes inthe tumor volume (A), and changes in the body weight (B), followingtreatment with 600 mg/kg of compound 1-1-1 of the present invention inmice.

FIG. 2 An example of the results of antitumor test, showing changes inthe tumor volume (A), and changes in the body weight (B), followingtreatment with 600 mg/kg of compound 2-1-1 of the present invention inmice.

EXAMPLES

The present invention will now be described in greater detail byexamples, but is in no way limited to these examples.

NMR analysis was made using JNM-EX270 (270 MHz) or JNM-GSX400 (400 MHz)produced by JEOL. NMR data were shown in ppm (parts per million) (δ),and referred to deuterium lock signals from sample solvents. Massspectrum data were obtained using JMS-DX303 or JMS-SX/SX102A produced byJEOL. Mass spectrum data from high-performance liquidchromatography-mass spectrometry were obtained using a micromassspectrometer (ZMD produced by Micromass) equipped with a gradienthigh-performance liquid chromatograph 996-600E produced by Waters, or amicromass spectrometer (Navigator produced by Finnigan) equipped with agradient high-performance liquid chromatograph Agilent 1100 produced byAgilent Technologies. The conditions used for high-performance liquidchromatography were any of the following:

Condition 1 for High-Performance Liquid Chromatography

Device: 996-600E produced by Waters;

Column: Combi ODS (ODS, 5 μm, 4.6 mm I.D.×50 mm, produced by Wako PureChemical Industries), COSMOSIL (ODS, 5 μm, 4.6 mm I.D.×50 mm, producedby Nacalai Tesque), or Inertsil C18 (ODS, 5 μm, 4.6 mm I.D.×50 mm,produced by GL Sciences);

Mobile phase: Water (A) containing 0.05% trifluoroacetic acid andacetonitrile (B) containing 0.05% trifluoroacetic acid;

Elution method: Stepwise solvent gradient elution with from 10% B to 95%B (3.5 min), from 95% B to 10% B (1 min), and kept with 10% B (0.5 min);and

Flow rate: 4.0 mL/min.

Condition 2 for High-Performance Liquid Chromatography

Device: 996-600E produced by Waters;

Column: Combi ODS (ODS, 5 μm, 4.6 mm I.D.×50 mm, produced by Wako PureChemical Industries), COSMOSIL (ODS, 5 μm, 4.6 mm I.D.×50 mm, producedby Nacalai Tesque), or Inertsil C18 (ODS, 5 μm, 4.6 mm I.D.×50 mm,produced by GL Sciences);

Mobile phase: Water (A) containing 0.05% trifluoroacetic acid andacetonitrile (B) containing 0.05% trifluoroacetic acid;

Elution method: Stepwise solvent gradient elution with from 30% B to 35%B (0.2 min), from 35% B to 98% B (3.3 min), from 98% B to 30% B (1 min),and kept with 30% B (0.5 min); and

Flow rate: 4.0 mL/min.

Condition 3 for High-Performance Liquid Chromatography

Device: Agilent 1100 produced by Agilent Technologies;

Column: Combi ODS (ODS, 5 μm, 4.6 mm I.D.×50 mm, produced by Wako PureChemical Industries), COSMOSIL (ODS, 5 μm, 4.6 mm I.D.×50 mm, producedby Nacalai Tesque), or Inertsil C18 (ODS, 5 μm, 4.6 mm I.D.×50 mm,produced by GL Sciences);

Mobile phase: Water (A) containing 0.05% trifluoroacetic acid andacetonitrile (B) containing 0.05% trifluoroacetic acid;

Elution method: Stepwise solvent gradient elution with from 10% B to 95%B (3.5 min), kept with 95% B (1 min), and from 95% B to 10% B (0.5 min);and Flow rate: 2.0 mL/min.

Condition 4 for High-Performance Liquid Chromatography

Device: Agilent 1100 produced by Agilent Technologies;

Column: Combi ODS (ODS, 5 μm, 4.6 mm I.D.×50 mm, produced by Wako PureChemical Industries), COSMOSIL (ODS, 5 μm, 4.6 mm I.D.×50 mm, producedby Nacalai Tesque), or Inertsil C18 (ODS, 5 μm, 4.6 mm I.D.×50 mm,produced by GL Sciences);

Mobile phase: Water (A) containing 0.05% trifluoroacetic acid andacetonitrile (B) containing 0.05% trifluoroacetic acid;

Elution method: Stepwise solvent gradient elution with from 10% B to 30%B (0.5 min), from 30% B to 98% B (3.5 min), kept with 98% B (1 min), andfrom 98% B to 10% B (1 min); and

Flow rate: 2.0 mL/min.

Condition 5 for High-Performance Liquid Chromatography

Device: 996-600E produced by Waters;

Column: Combi ODS (ODS, 5 μm, 4.6 mm I.D.×50 mm, produced by Wako PureChemical Industries), COSMOSIL (ODS, 5 μm, 4.6 mm I.D.×50 mm, producedby Nacalai Tesque), or Inertsil C18 (ODS, 5 μm, 4.6 mm I.D.×50 mm,produced by GL Sciences);

Mobile phase: Water (A) containing 0.05% trifluoroacetic acid andacetonitrile (B) containing 0.05% trifluoroacetic acid;

Elution method: Stepwise solvent gradient elution with from 1% B to 95%B (3.5 min), from 95% B to 1% B (1 min), and kept with 1% B (0.5 min);and Flow rate: 4.0 mL/min.

Purification of the compound by a micromass spectrometer (ZMD producedby Micromass) equipped with a gradient high-performance liquidchromatograph 996-600E produced by Waters was performed based on thedetection of signals from a mass spectrometer under the followingconditions:

Column: Combi ODS (ODS, 5 μm, 28 mm I.D.×50 mm, produced by Wako PureChemical Industries);

Mobile phase: Water (A) containing 0.05% trifluoroacetic acid andacetonitrile (B) containing 0.05% trifluoroacetic acid;

Elution method: Stepwise solvent gradient elution, kept with 10% B (0.5min), from 10% B to 95% B (7.5 min), kept with 95% B (0.5 min), and from95% B to 10% B (1.5 min); and

Flow rate: 35 mL/min.

Commercially available reagents were used without further purification.Room temperature refers to a range of from 20 to 25° C. All nonaqueousreactions were carried out under a nitrogen or argon atmosphere.Concentration or solvent distilling-off under reduced pressure refers tothe use of a rotary evaporator.

In the preparation of compounds, functional groups were protected byprotective groups, where necessary, and after preparation of targetmolecules, these protective groups were removed. Operations forselection and detachment of the protective groups were performed by themethods described in “Greene and Wuts, “Protective Groups in OrganicSynthesis” (2nd Ed., John Wiley & Sons, 1991)”.

Kaiser test conducted in the Examples to confirm the presence of aminogroups in the product was performed in accordance with the proceduredescribed in J. M. Stewart, J. D. Young, Solid Phase Peptide Synthesis,2nd Ed., page 105 (Pierce Chemical Company, 1984).

Example 1-1-1 Production of 3-N-(4-chlorophenyl)-4-methoxyisophthalamide(Compound 1-1-1)

Step A: Preparation of methyl 5-bromo-2-methoxybenzoate (CAS RegistryNumber: 7120-41-4)

5-Bromo-2-hydroxybenzoic acid (25 g) and 40 g of potassium carbonatewere suspended in 300 mL of acetone. Dimethyl sulfate (28 mL) was addedto the suspension, and the mixture was stirred for 19 hours under refluxwith heating. The reaction mixture was cooled to room temperature,whereafter the insolubles were separated by filtration, and washed withethyl acetate. The filtrate and the washings were combined, and acetoneand ethyl acetate were distilled off under reduced pressure. Theresulting residue was dissolved in 300 mL of ethyl acetate. Water (300mL) was added to the solution, and the organic layer was separated,followed by extracting the aqueous layer with 200 mL of ethyl acetate.After the respective organic layers were combined, the combined organiclayer was washed with a saturated aqueous solution of sodium chloride,and dried over anhydrous sodium sulfate. The anhydrous sodium sulfatewas separated by filtration, and then washed with ethyl acetate. Thefiltrate and the washings were combined, and ethyl acetate was distilledoff under reduced pressure to obtain 30 g of methyl5-bromo-2-methoxybenzoate.

¹H-NMR (400 MHz, CDCl₃) δ 3.89 (3H, s), 6.87 (1H, d, J=8.8 Hz), 7.55(1H, dd, J=8.8 Hz, 2.9 Hz), 7.90 (1H, d, J=2.9 Hz).

ESI (LC/MS positive mode) m/z 245, 247 (M+H⁺); retention time 3.18 min(Condition 1 for high-performance liquid chromatography).

Step B: Preparation of 5-bromo-2-methoxybenzoic acid (CAS RegistryNumber: 2476-35-9)

Methyl 5-bromo-2-methoxybenzoate (14.7 g) obtained in step A wasdissolved in 100 mL of methanol. To the solution, 40 mL of a 20% aqueoussolution of potassium hydroxide was added, and the mixture was stirredfor 2 hours at 80° C. The reaction solution was cooled to 0° C., andthen adjusted to pH of about 3 with the use of 11 mL of concentratedhydrochloric acid. The precipitate was separated by filtration, washedwith water, and then dried over diphosphorus pentoxide under reducedpressure to obtain 10.9 g (85%) of 5-bromo-2-methoxybenzoic acid.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.81 (3H, s), 7.11 (1H, d, J=9.0 Hz), 7.67(1H, dd, J=9.0 Hz, 2.6 Hz), 7.72 (1H, d, J=2.6 Hz), 12.94 (1H, bs).

ESI (LC/MS positive mode) m/z 231, 233 (M+H⁺); retention time 2.66 min(Condition 1 for high-performance liquid chromatography).

Step C: Preparation of 5-bromo-N-(4-chlorophenyl)-2-methoxybenzamide

5-Bromo-2-methoxybenzoic acid (20 g) obtained in step B and 0.34 mL ofN,N-dimethylformamide were dissolved in 380 mL of dichloromethane, andthe solution was cooled to 0° C. This solution was stirred for 30minutes at 0° C., with oxalyl chloride (11.3 mL) being added little bylittle thereto, and then the mixture was stirred for 3 hours at roomtemperature. The reaction mixture was distilled under reduced pressureand dried to obtain a light yellow solid. This solid was added, with theuse of 120 mL of dichloromethane, to a solution of 11.1 g of4-chloroaniline and 45 mL of N,N-diisopropylethylamine dissolved in 380mL of dichloromethane. The mixture was stirred for 2 hours and a half atroom temperature, and then 300 mL of water was added. The organic layerwas separated, and the aqueous layer was extracted twice with 100 mL ofdichloromethane. After the respective organic layers were combined, thecombined organic layer was washed with 200 mL of a saturated aqueoussolution of sodium bicarbonate, and dried over anhydrous sodium sulfate.The anhydrous sodium sulfate was separated by filtration, and thenwashed with dichloromethane. The filtrate and the washings werecombined, dichloromethane was distilled off under reduced pressure, andthe resulting residue was washed with methanol. The resulting solid wasdried under reduced pressure to obtain 23.6 g (80%) of5-bromo-N-(4-chlorophenyl)-2-methoxybenzamide.

¹H-NMR (400 MHz, CDCl₃) δ 4.06 (3H, s), 6.93 (1H, d, J=8.8 Hz), 7.33(2H, d, J=8.8 Hz), 7.59 (1H, dd, J=8.8 Hz, 2.9 Hz), 7.61 (2H, d, J=8.8Hz), 8.39 (1H, d, J=2.9 Hz), 9.70 (1H, bs).

ESI (LC/MS positive mode) m/z 340, 342 (M+H⁺); retention time 3.49 min(Condition 2 for high-performance liquid chromatography).

Step D: Preparation of 5-cyano-N-(4-chlorophenyl)-2-methoxybenzamide

5-Bromo-N-(4-chlorophenyl)-2-methoxybenzamide (9.0 g) obtained in stepC, and 7.8 g of zinc cyanide were dissolved in 100 mL ofN,N-dimethylformamide. The N,N-dimethylformamide was degassed underreduced pressure, and then the interior of the reactor was purged withnitrogen. After 2.3 g of tetrakistriphenylphosphine palladium was added,the N,N-dimethylformamide was degassed again under reduced pressure, andthen the interior of the reactor was purged with argon. This solutionwas stirred for 2 hours and a half at 100° C., whereafter the solventwas distilled off under reduced pressure, and the residue was dissolvedin ethyl acetate. The insolubles were removed by filtration, and washedwith ethyl acetate. The filtrate and the washings were combined, 100 mLof water was added, and then the organic layer was separated. Theaqueous layer was extracted twice with ethyl acetate. After therespective organic layers were combined, the combined organic layer waswashed with a saturated aqueous solution of sodium chloride, and driedover anhydrous sodium sulfate. The anhydrous sodium sulfate wasseparated by filtration, and then washed with ethyl acetate. Thefiltrate and the washings were combined, and ethyl acetate was distilledoff under reduced pressure. The resulting residue was washed withmethanol. The resulting solid was dried under reduced pressure to obtain4.9 g (64%) of 5-cyano-N-(4-chlorophenyl)-2-methoxybenzamide.

¹H-NMR (400 MHz, CDCl₃) δ 4.15 (3H, s), 7.14 (1H, d, J=8.8 Hz), 7.34(2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.79 (1H, dd, J=8.8 Hz, 2.4Hz), 8.58 (1H, d, J=2.4 Hz), 9.53 (1H, bs).

ESI (LC/MS positive mode) m/z 287, 289 (M+H⁺); retention time 3.54 min(Condition 1 for high-performance liquid chromatography).

Step E: Preparation of 3-N-(4-chlorophenyl)-4-methoxyisophthalamide(Compound 1-1-1)

5-Cyano-N-(4-chlorophenyl)-2-methoxybenzamide (9.8 g) obtained in step Dwas dissolved in 80 mL of dimethyl sulfoxide, and the solution wascooled in a water bath. A solution prepared from 17.4 mL of a 30%aqueous solution of hydrogen peroxide and 9.5 g of potassium carbonatewas added dropwise to the solution. After stirring for 1 hour, themixture was poured into 800 mL of cold water. The precipitate formed wasseparated by filtration, washed with cold water, and then dried overdiphosphorus pentoxide under reduced pressure to obtain 10.3 g (99%) of3-N-(4-chlorophenyl)-4-methoxyisophthalamide.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.92 (3H, s), 7.24 (1H, d, J=8.8 Hz), 7.29(1H, bs), 7.40 (2H, d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 7.97 (1H, bs),8.03 (1H, dd, J=8.8 Hz, 2.2 Hz), 8.12 (1H, d, J=2.2 Hz), 10.31 (1H, s).

ESI (LC/MS positive mode) m/z 305, 307 (M+H⁺); retention time 2.91 min(Condition 1 for high-performance liquid chromatography).

Example 1-1-2 Production of 3-N-(4-chlorophenyl)-4-propoxyisophthalamide(Compound 1-1-2)

3-N-(4-Chlorophenyl)-4-methoxyisophthalamide (compound 1-1-1) (50 mg)obtained in step E of Example 1-1-1 was suspended in 5 mL ofdichloromethane. With the suspension being stirred, 1.0 mL of a 0.16 Msolution of boron tribromide in dichloromethane was added dropwise atroom temperature. After stirring for 1 hour, 0.7 mL of a 0.16 M solutionof boron tribromide in dichloromethane was added dropwise at roomtemperature, and the mixture was further stirred for 30 minutes. Thereaction solution was diluted with 50 mL of ethyl acetate, then thedilution was washed with 0.1 M hydrochloric acid and then with asaturated aqueous solution of sodium chloride, and dried over anhydroussodium sulfate. Sodium sulfate was separated by filtration, and thefiltrate was concentrated under reduced pressure. The residue was driedunder reduced pressure to obtain 44 mg of a colorless solid. This solid(10 mg) and 9 mg of potassium carbonate were suspended in 1 mL ofN,N-dimethylformamide. Propyl iodide (3 μL) was added to the suspension,and the mixture was stirred for 1 hour at 70° C. The reaction solutioncooled to room temperature was diluted with 50 mL of ethyl acetate,washed with distilled water and then with a saturated aqueous solutionof sodium chloride, and dried over anhydrous sodium sulfate. Sodiumsulfate was separated by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified using a micromassspectrometer (ZMD produced by Micromass) equipped with a gradienthigh-performance liquid chromatograph 996-600E produced by Waters, toobtain 6 mg (52%) of 3-N-(4-chlorophenyl)-4-propoxyisophthalamide as awhite solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 0.96 (3H, t, J=7.6 Hz), 1.74-1.80 (2H, m),4.11 (2H, t, J=6.2 Hz), 7.22 (1H, d, J=8.8 Hz), 7.30 (1H, bs), 7.41 (2H,d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 7.99 (1H, bs), 8.01 (1H, dd, J=8.8Hz, 2.4 Hz), 8.14 (1H, d, J=2.4 Hz), 10.30 (1H, bs).

ESI (LC/MS positive mode) m/z 333, 335 (M+H⁺); retention time 3.29 min(Condition 1 for high-performance liquid chromatography).

Example 1-1-3 Production of4-aryloxy-3-N-(4-chlorophenyl)-isophthalamide (Compound 1-1-3)

The captioned compound was synthesized from3-N-(4-chlorophenyl)-4-methoxyisophthalamide and allyl bromide by thesame procedure as in the manufacturing method described in Example1-1-2.

¹H-NMR (400 MHz, DMSO-d₆) δ 4.74 (2H, d, J=4.8 Hz), 5.25 (1H, dd, J=10.8Hz, 1.2 Hz), 5.41 (1H, dd, J=10.8 Hz, 1.2 Hz), 6.02-6.11 (1H, m), 7.23(1H, d, J=8.8 Hz), 7.32 (1H, bs), 7.41 (2H, d, J=8.8 Hz), 7.75 (2H, d,J=8.8 Hz), 7.99-8.02 (2H, m), 8.11 (1H, d, J=2.0 Hz), 10.36 (1H, bs).

ESI (LC/MS positive mode) m/z 331, 333 (M+H⁺); retention time 3.17 min(Condition 1 for high-performance liquid chromatography).

Example 1-1-4 Production of3-N-(4-chlorophenyl)-4-(2-pentenyloxy)-isophthalamide (Compound 1-1-4)

The captioned compound was synthesized from3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-pentene bythe same procedure as in the manufacturing method described in Example1-1-2.

¹H-NMR (270 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.6 Hz), 1.99-2.09 (2H, m),4.68 (2H, d, J=5.3 Hz), 5.70 (1H, dt, J=15.5 Hz, 5.3 Hz), 5.93 (1H, dt,J=15.5 Hz, 6.3 Hz), 7.23 (1H, d, J=8.9 Hz), 7.30 (1H, bs), 7.42 (2H, d,J=8.9 Hz), 7.75 (2H, d, J=8.9 Hz), 7.98-8.03 (2H, m), 8.14 (1H, d, J=2.0Hz), 10.34 (1H, bs).

ESI (LC/MS positive mode) m/z 291, 293 (M+H⁺); retention time 3.70 min(Condition 1 for high-performance liquid chromatography).

Example 1-1-5 Production of4-(2-butynyloxy)-3-N-(4-chlorophenyl)-isophthalamide (Compound 1-1-5)

The captioned compound was synthesized from3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-butyne by thesame procedure as in the manufacturing method described in Example1-1-2.

¹H-NMR (270 MHz, DMSO-d₆) δ 1.84 (3H, d, J=2.3 Hz), 4.94 (2H, d, J=2.3Hz), 7.27 (1H, d, J=8.9 Hz), 7.33 (1H, bs), 7.41 (2H, d, J=8.9 Hz), 7.75(2H, d, J=8.9 Hz), 7.98-8.11 (2H, m), 8.11 (1H, d, J=2.3 Hz), 10.36 (1H,bs).

ESI (LC/MS positive mode) m/z 343, 345 (M+H⁺); retention time 3.32 min(Condition 1 for high-performance liquid chromatography).

Example 1-1-6 Production of 4-butoxy-3-N-(4-chlorophenyl)-isophthalamide(Compound 1-1-6)

The captioned compound was synthesized from3-N-(4-chlorophenyl)-4-methoxyisophthalamide and butyl bromide by thesame procedure as in the manufacturing method described in Example1-1-2.

¹H-NMR (270 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.4 Hz), 1.35-1.49 (2H, m),1.68-1.79 (2H, m), 4.15 (2H, t, J=6.3 Hz), 7.24 (1H, d, J=8.6 Hz), 7.30(1H, bs), 7.42 (2H, d, J=8.9 Hz), 7.75 (2H, d, J=8.9 Hz), 7.98 (1H, bs),8.01 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.14 (1H, d, J=2.3 Hz), 10.28 (1H, bs).

ESI (LC/MS positive mode) m/z 347, 349 (M+H⁺); retention time 3.61 min(Condition 1 for high-performance liquid chromatography).

Example 1-1-7 Production of4-(2-chloroethoxy)-3-N-(4-chlorophenyl)-isophthalamide (Compound 1-1-7)

The captioned compound was synthesized from3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-chloroethaneby the same procedure as in the manufacturing method described inExample 1-1-2.

¹H-NMR (270 MHz, DMSO-d₆) δ 4.04 (2H, t, J=5.1 Hz), 4.47 (2H, t, J=5.1Hz), 7.28 (1H, d, J=8.9 Hz), 7.34 (1H, bs), 7.43 (2H, d, J=8.9 Hz), 7.78(2H, d, J=8.9 Hz), 8.02-8.06 (2H, m), 8.25 (1H, d, J=2.0 Hz), 10.23 (1H,bs).

ESI (LC/MS positive mode) m/z 353, 355 (M+H⁺); retention time 3.25 min(Condition 1 for high-performance liquid chromatography).

Example 1-1-8 Production of3-N-(4-chlorophenyl)-4-cyclopropylmethoxy-isophthalamide (Compound1-1-8)

The captioned compound was synthesized from3-N-(4-chlorophenyl)-4-methoxyisophthalamide and(bromomethyl)cyclopropane by the same procedure as in the manufacturingmethod described in Example 1-1-2.

¹H-NMR (270 MHz, DMSO-d₆) δ 0.41 (2H, dd, J=9.6 Hz, 4.6 Hz), 0.54-0.60(2H, m), 1.24-1.40 (1H, m), 4.05 (2H, d, J=6.9 Hz), 7.21 (1H, d, J=8.9Hz), 7.30 (1H, bs), 7.43 (2H, d, J=8.9 Hz), 7.78 (2H, d, J=8.9 Hz),8.00-8.03 (2H, m), 8.23 (1H, d, J=2.3 Hz), 10.35 (1H, bs).

ESI (LC/MS positive mode) m/z 345, 347 (M+H⁺); retention time 3.48 min(Condition 1 for high-performance liquid chromatography).

Example 1-1-9 Production ofN-3-(4-chlorophenyl)-4-ethynyl-isophthalamide (Compound 1-1-9)

Step A: Preparation of trifluoromethanesulfonic acid4-carbamoyl-2-(4-chlorophenylcarbamoyl)-phenyl ester (Compound 1-1-9-A)

3-N-(4-Chlorophenyl)-4-methoxyisophthalamide (2.56 g) obtained in step Eof Example 1-1-1 was suspended in 136 mL of dichloromethane. With thesuspension being stirred, a 0.16 M solution of boron tribromide indichloromethane was added dropwise at room temperature until thereaction was completed. The reaction solution was diluted with 500 mL ofethyl acetate, then the dilution was washed with 0.1 M hydrochloric acidand then with a saturated aqueous solution of sodium chloride, and driedover anhydrous sodium sulfate. Sodium sulfate was separated byfiltration, and the filtrate was concentrated under reduced pressure.The residue was dried under reduced pressure to obtain 2.0 g of a whitesolid. This solid (50 mg) was dissolved in 2 mL ofN,N-dimethylformamide. To this solution, there were added 72 μL oftriethylamine and 92 mg of N-phenylbis(trifluoromethanesulfonimide), andthe mixture was stirred for 1 hour at room temperature. The reactionsolution was diluted with 50 mL of ethyl acetate, then the dilution waswashed with saturated ammonium chloride, and dried over anhydrous sodiumsulfate. Sodium sulfate was separated by filtration, and the filtratewas concentrated under reduced pressure. The residue was washed with 10mL of dichloromethane, and dried under reduced pressure to obtain 38 mg(52%) of trifluoromethanesulfonic acid4-carbamoyl-2-(4-chlorophenylcarbamoyl)-phenyl ester.

¹H-NMR (270 MHz, DMSO-d₆) δ 7.46 (2H, d, J=8.9 Hz), 7.70-7.75 (4H, m),8.18 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.25 (1H, bs), 8.32 (1H, d, J=2.3 Hz),10.88 (1H, bs).

ESI (LC/MS positive mode) m/z 423, 425 (M+H⁺); retention time 3.40 min(Condition 1 for high-performance liquid chromatography).

Step B: Preparation of N-3-(4-chlorophenl)-4-ethynyl-isophthalamide(Compound 1-1-9)

Trifluoromethanesulfonic acid4-carbamoyl-2-(4-chlorophenylcarbamoyl)-phenyl ester (40 mg) obtained instep A was dissolved in 3 mL of N,N-dimethylformamide. To this solution,0.5 ml of triethylamine, 6 mg of copper (I) iodide, 134 μl of TMSacetylene, and 33 mg of tetrakis(triphenylphosphine)palladium wereadded, followed by stirring the mixture for 3 hours at 75° C. Thereaction solution was filtered through Celite, and the filtrate wasdiluted with 60 mL of ethyl acetate. This solution was washed withdistilled water and then with a saturated aqueous solution of sodiumchloride, and dried over anhydrous sodium sulfate. Sodium sulfate wasseparated by filtration, and the filtrate was concentrated under reducedpressure. The residue was dissolved in 3 mL of methanol, 20 mg ofpotassium carbonate was added to this solution, and the mixture wasstirred for 1 hour at room temperature. The reaction solution wasdiluted with 50 mL of ethyl acetate, and then was washed with saturatedammonium chloride, and dried over anhydrous sodium sulfate. Sodiumsulfate was separated by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by thin layerchromatography (hexane:ethyl acetate=1:4) to obtain 5 mg (17%) ofN-3-(4-chlorophenyl)-4-ethynyl-isophthalamide.

ESI (LC/MS positive mode) m/z 299, 301 (M+H⁺); 340 (M+CH₃CN+H⁺);retention time 2.59 min (Condition 3 for high-performance liquidchromatography).

Example 1-1-10 Production of[4-carbamoyl-2-(4-trifluoromethoxy-phenylcarbamoyl)-phenoxy]-acetic acidethyl ester

The captioned compound was synthesized from3-N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamide and ethylbromoacetate by the same procedure as in the manufacturing methoddescribed in Example 1-1-2.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.22 (3H, t, J=6.8 Hz), 4.23 (2H, q, J=6.8Hz), 5.04 (2H, s), 7.25 (1H, d, J=8.8 Hz), 7.36 (1H, bs), 7.40 (2H, d,J=8.8 Hz), 7.92 (2H, d, J=9.3 Hz), 8.03 (2H, dd, J=8.8 Hz, 2.0 Hz), 8.36(1H, d, J=2.0 Hz), 10.53 (1H, bs).

ESI (LC/MS positive mode) m/z 427 (M+H⁺); retention time 2.78 min(Condition 2 for high-performance liquid chromatography).

Example 1-2-1 Preparation of3-N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamide (Compound 1-2-1)

Step A: Preparation of ethyl 3-chloromethyl-4-methoxybenzoate

Ethyl 4-methoxybenzoate (28.0 mL) and 26.0 mL of methoxymethyl chloridewere dissolved in 500 mL of dichloromethane, and the solution was cooledto 0° C. To this solution, 10.0 mL of tin (IV) chloride was addeddropwise over 15 minutes, and then the mixture was stirred for 5 hours.The reaction mixture was poured into 1 L of water, and the organic layerwas separated, whereafter the aqueous layer was extracted twice withdichloromethane. The organic layer was washed with a saturated aqueoussolution of sodium chloride, and dried over anhydrous sodium sulfate.The anhydrous sodium sulfate was separated by filtration, and washedwith dichloromethane. The filtrate and the washings were combined, anddichloromethane was distilled off under reduced pressure. The resultingresidue was recrystallized from a mixture of n-hexane and ethyl acetate.The resulting crystals were separated by filtration, then washed withn-hexane, and dried under reduced pressure to obtain 23.8 g (60%) ofethyl 3-chloromethyl-4-methoxybenzoate.

¹H-NMR (400 MHz, CDCl₃) δ 1.39 (3H, t, J=7.0 Hz), 3.95 (3H, s), 4.36(2H, q, J=7.0 Hz), 4.66 (2H, s), 6.92 (1H, d, J=8.3 Hz), 8.03 (1H, dd,J=8.3 Hz, 2.1 Hz), 8.05 (1H, d, J=2.1 Hz).

ESI (LC/MS positive mode) m/z 229, 231 (M+H⁺); retention time 2.85 min(Condition 2 for high-performance liquid chromatography).

Step B: Preparation of5-ethoxycarbonyl-2-methoxybenzylhexamethylenetetraminium chloride

Ethyl 3-chloromethyl-4-methoxybenzoate (8.2 g) obtained in step A and5.3 g of hexamethylenetetramine were dissolved in 30 mL of toluene, andstirred for 6 hours at 100° C., followed by cooling the solution to 0°C. The precipitate was separated by filtration, then washed with ethylacetate, and dried under reduced pressure to obtain 12.0 g (91%) of5-ethoxycarbonyl-2-methoxybenzylhexamethylenetetraminium chloride.

ESI (LC/MS positive mode) m/z 333 (M⁺-Cl); retention time 1.88 min(Condition 1 for high-performance liquid chromatography).

Step C: Preparation of ethyl 3-formyl-4-methoxybenzoate (CAS RegistryNumber: 122136-03-2)

5-Ethoxycarbonyl-2-methoxybenzylhexamethylenetetraminium chloride (12.0g) obtained in step B was dissolved in 24 mL of a 50% aqueous solutionof acetic acid, and the solution was stirred for 4.5 hours at 100° C.The reaction mixture was cooled to about 40° C., 48 mL of water wasadded, and the mixture was stirred for 67 hours at room temperature. Theprecipitate was separated by filtration, washed with water, and thendried over diphosphorus pentoxide under reduced pressure to obtain 3.5 g(52%) of ethyl 3-formyl-4-methoxybenzoate.

¹H-NMR (400 MHz, CDCl₃) δ 1.40 (3H, t, J=7.1 Hz), 4.01 (3H, s), 4.37(2H, q, J=7.1 Hz), 7.05 (1H, d, J=8.8 Hz), 8.26 (1H, dd, J=8.8 Hz, 2.1Hz), 8.51 (1H, d, J=2.1 Hz), 10.46 (1H, s).

ESI (LC/MS positive mode) m/z 209 (M+H⁺); retention time 3.08 min(Condition 1 for high-performance liquid chromatography).

Step D: Preparation of 1-ethyl 4-methoxyisophthalate

Ethyl 3-formyl-4-methoxybenzoate (5.0 g) obtained in step C, 20 mL of2-methyl-2-butene, and 2.9 g of sodium dihydrogenphosphate weredissolved in a mixed solution of 20 mL of water and 50 mL of t-butylalcohol, whereafter the solution was cooled to 0° C. To this solution,7.4 g of sodium chlorite was added little by little, and then themixture was stirred for 1 hour and a half at room temperature. Thereaction mixture was cooled to 0° C., and then 23 mL of 1 M hydrochloricacid was added for acidification, followed by extracting the mixture 3times with ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous sodiumsulfate. The anhydrous sodium sulfate was separated by filtration, andthen washed with ethyl acetate. The filtrate and the washings werecombined, and ethyl acetate was distilled off under reduced pressure.The resulting residue was washed with an n-hexane solution containing asmall amount of diethyl ether, and dried under reduced pressure toobtain 5.1 g (96%) of 1-ethyl 4-methoxyisophthalate.

¹H-NMR (400 MHz, CDCl₃) δ 1.40 (3H, t, J=7.0 Hz), 4.15 (3H, s), 4.39(2H, q, J=7.0 Hz), 7.12 (1H, d, J=8.8 Hz), 8.27 (1H, dd, J=8.8 Hz, 2.0Hz), 8.84 (1H, d, J=2.0 Hz).

ESI (LC/MS positive mode) m/z 225 (M+H⁺); retention time 2.54 min(Condition 1 for high-performance liquid chromatography).

Step E: Preparation of ethylN-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamate

1-Ethyl 4-methoxyisophthalate (150 mg) obtained in step D, and 3 μL ofN,N-dimethylformamide were dissolved in 10 mL of dichloromethane, andthe solution was cooled to 0° C. To this solution, 88 μL of oxalylchloride was added little by little, and the mixture was stirred for 20minutes at 0° C., followed by stirring the mixture for 16 hours at roomtemperature. The reaction mixture was distilled under reduced pressure,and dried to obtain a light yellow solid. This solid was dissolved in 9mL of dichloromethane, and 3 mL of the solution was added to a solutionof 42 mg of 4-trifluoromethoxyaniline and 123 μL ofN,N-diisopropylethylamine dissolved in 2 mL of dichloromethane. Themixture was stirred for 6 hours at room temperature, and thendichloromethane was distilled off under reduced pressure. The resultingresidue was purified by column chromatography (5 g of silica gel) usinga 1:1 mixture of dichloromethane and n-hexane as an elution solvent,thereby obtaining 79 mg (92%) of ethylN-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamate.

¹H-NMR (400 MHz, CDCl₃) δ 1.41 (3H, t, J=7.2 Hz), 4.14 (3H, s), 4.39(2H, q, J=7.2 Hz), 7.10 (1H, d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.71(2H, d, J=8.8 Hz), 8.22 (1H, dd, J=8.8 Hz, 2.3 Hz), 8.94 (1H, d, J=2.3Hz), 9.66 (1H, bs).

ESI (LC/MS positive mode) m/z 384 (M+H⁺); retention time 3.42 min(Condition 2 for high-performance liquid chromatography).

Step F: Preparation ofN-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamic acid

Ethyl N-(4-trifluoromethoxyphenyl)-4-methoxy-isophthalamate (51 mg)obtained in step E was dissolved in 2 mL of methanol, and 0.8 mL of a20% aqueous solution of potassium hydroxide was added. The resultingsolution was stirred for 30 minutes at 80° C., and then cooled to roomtemperature. One M hydrochloric acid (3 mL) was used to adjust thesolution to pH of about 3. Then, the resulting aqueous solution wasextracted with ethyl acetate. The respective organic layers werecombined, whereafter the combined organic layer was washed with asaturated aqueous solution of sodium chloride, and dried over anhydroussodium sulfate. The anhydrous sodium sulfate was separated byfiltration, and washed with ethyl acetate. The filtrate and the washingswere combined, and ethyl acetate was distilled off under reducedpressure to obtain 48 mg (100%) ofN-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamic acid.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.95 (3H, s), 7.29 (1H, d, J=8.8 Hz), 7.36(2H, d, J=8.8 Hz), 7.84 (2H, d, J=8.8 Hz), 8.07 (1H, dd, J=8.8 Hz, 2.3Hz), 8.12 (1H, d, J=2.3 Hz), 10.38 (1H, s), 12.91 (1H, s).

ESI (LC/MS positive mode) m/z 356 (M+H⁺); retention time 3.36 min(Condition 1 for high-performance liquid chromatography).

Step G: Preparation of3-N-(4-trifluoro-methoxyphenyl)-4-methoxyisophthalamide (Compound 1-2-1)

N-(4-Trifluoromethoxyphenyl)-4-methoxyisophthalamic acid (48 mg)obtained in step F, 11 mg of ammonium chloride, 25 mg ofbenzotriazol-1-ol monohydrate, and 31 mg of(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride were dissolved in2 mL of N,N-dimethylformamide, and 70 μL of N,N-diisopropylethylaminewas added. This solution was stirred overnight at room temperature, andthen the solvent was distilled off under reduced pressure. The resultingresidue was purified by column chromatography (5 g of silica gel, 2 g ofaminopropyl-modified silica gel) using a 100:1 mixture ofdichloromethane and methanol as an elution solvent, thereby obtaining 45mg (96%) of 3-N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamide.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.92 (3H, s), 7.24 (1H, d, J=8.8 Hz), 7.31(1H, bs), 7.37 (2H, d, J=9.0 Hz), 7.85 (2H, d, J=9.0 Hz), 7.99 (1H, bs),8.04 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.12 (1H, d, J=2.0 Hz), 10.39 (1H, s).

ESI (LC/MS positive mode) m/z 355 (M+H⁺); retention time 3.07 min(Condition 1 for high-performance liquid chromatography).

Example 1-2-2 Production of3-N-(4-tert-butylphenyl)-4-methoxyisophthalamide (Compound 1-2-2)

The captioned compound was synthesized using 4-tert-butylaniline insteadof 4-chloroaniline in accordance with the methods described in steps E,F and G of Example 1-2-1.

ESI (LC/MS positive mode) m/z 327 (M+H⁺); retention time 3.25 min(Condition 1 for high-performance liquid chromatography).

Example 1-2-3 Production of3-N-(4-chlorophenyl)-1-N-cyclopentyl-4-methoxyisophthalamide (Compound1-2-3)

Step A: Preparation of ethyl N-(4-chlorophenyl)-4-methoxyisophthalamate

1-Ethyl 4-methoxyisophthalate (100 mg) obtained in step D of Example1-2-1, and 2 μL of N,N-dimethylformamide were dissolved in 5 mL ofdichloromethane, and the solution was cooled to 0° C. To this solution,59 μL of oxalyl chloride was added little by little, and the mixture wasstirred for 20 minutes at 0° C., followed by stirring the mixture for 16hours at room temperature. The reaction mixture was distilled underreduced pressure, and dried to obtain a light yellow solid. This solidwas dissolved in 3 mL of dichloromethane, and the solution was added toa solution of 63 mg of 4-chloroaniline and 234 μL ofN,N-diisopropylethylamine dissolved in 2 mL of dichloromethane. Themixture was stirred for 3 hours at room temperature, and thendichloromethane was distilled off under reduced pressure. The resultingresidue was purified by column chromatography (5 g of silica gel) usinga 1:1 mixture of dichloromethane and n-hexane as an elution solvent,thereby obtaining 134 mg (94%) of ethylN-(4-chlorophenyl)-4-methoxyisophthalamate.

¹H-NMR (270 MHz, DMSO-d₆) δ 1.32 (3H, t, J=7.3 Hz), 3.96 (3H, s), 4.31(2H, q, J=7.3 Hz), 7.31 (1H, d, J=8.9 Hz), 7.40 (2H, d, J=8.8 Hz), 7.77(2H, d, J=8.8 Hz), 8.09 (1H, dd, J=8.9 Hz, 2.3 Hz), 8.15 (1H, d, J=2.3Hz), 10.3 (1H, s).

ESI (LC/MS positive mode) m/z 334, 336 (M+H⁺); retention time 3.28 min(Condition 2 for high-performance liquid chromatography).

Step B: Preparation of N-(4-chlorophenyl)-4-methoxyisophthalic acid

Ethyl N-(4-chlorophenyl)-4-methoxyisophthalamate (11.8 g) obtained instep A was dissolved in 200 mL of methanol and 60 mL of a 20% aqueoussolution of potassium hydroxide. The resulting solution was stirred for30 minutes at 80° C., and then cooled to room temperature. One Mhydrochloric acid was used to adjust the solution to pH of about 3.Then, the resulting precipitate was separated by filtration, washed withwater, and dried over calcium chloride under reduced pressure, therebyobtaining 10.7 g (99%) of N-(4-chlorophenyl)-4-methoxyisophthalic acid.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.95 (3H, s), 7.28 (1H, d, J=8.6 Hz), 7.40(2H, d, J=8.9 Hz), 7.76 (2H, d, J=8.9 Hz), 8.07 (1H, dd, J=8.6 Hz, 2.3Hz), 8.12 (1H, d, J=2.3 Hz), 10.3 (1H, s), 12.9 (1H, s).

ESI (LC/MS positive mode) m/z 306, 308 (M+H⁺); retention time 2.28 min(Condition 2 for high-performance liquid chromatography).

Step C: Preparation of3-N-(4-chlorophenyl)-1-N-cyclopentyl-4-methoxyisophthalamide (Compound1-2-3)

N-(4-Chlorophenyl)-4-methoxyisophthalic acid (140 mg) obtained in step Bwas dissolved in 20 μL of N,N-dimethylformamide and 4 mL ofdichloromethane, and the solution was cooled to 0° C. To this solution,60 μL of oxalyl chloride was added little by little, and the mixture wasstirred for 20 minutes at 0° C., followed by stirring the mixture for 30minutes at room temperature. The reaction mixture was distilled underreduced pressure, and dried to obtain a light yellow solid, which wasdissolved in 3 mL of dichloromethane. To 500 μL of this solution, therewas added 500 μL of a solution of 7.6 mg of cyclopentylamine and 20 μLof N,N-diisopropylethylamine dissolved in dichloromethane, followed bystirring the mixture for 30 minutes at room temperature. Water (1 mL)was added to separate the organic layer, and the organic layer wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain 3.8 mg (13%) ofN-3-(4-chlorophenyl)-N-1-cyclopentyl-4-methoxy-isophthalamide.

¹H-NMR (270 MHz, CDCl₃) δ 1.40-1.60 (2H, m), 1.60-1.85 (4H, m),2.00-2.20 (2H, m), 4.13 (3H, s), 4.41 (1H, dd, J=14 Hz, 2.9 Hz), 6.24(1H, bd, J=6.9 Hz), 7.13 (1H, d, J=8.9 Hz), 7.34 (2H, d, J=8.9 Hz), 7.63(2H, d, J=8.9 Hz), 8.17 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.50 (1H, d, J=2.6Hz), 9.77 (1H, bs).

ESI (LC/MS positive mode) m/z 373, 375 (M+H⁺); retention time 3.24 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-4

Production of N-3-(4-chlorophenyl)-4-methoxy-N-1-methyl-isophthalamide(Compound 1-2-4)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and methylaminehydrochloride by the same procedure as in the manufacturing methoddescribed in step G of Example 1-2-1.

¹H-NMR (270 MHz, CDCl₃) δ 3.01 (3H, d, J=5.0 Hz), 4.12 (3H, s), 6.38(1H, bs), 7.12 (1H, d, J=8.6 Hz), 7.33 (2H, d, J=8.9 Hz), 7.62 (2H, d,J=8.9 Hz), 8.15 (1H, dd, J=8.6 Hz, 2.7 Hz), 8.53 (1H, d, J=2.7 Hz), 9.75(1H, bs).

ESI (LC/MS positive mode) 319, 321 (M+H⁺); retention time 2.66 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-5 Production ofN-3-(4-chlorophenyl)-4-methoxy-N-1-ethyl-isophthalamide (Compound 1-2-5)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and ethylaminehydrochloride by the same procedure as in the manufacturing methoddescribed in step C of Example 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 1.26 (3H, t, J=4.5 Hz), 3.51 (2H, dd, J=7.3Hz, 4.5 Hz), 4.13 (3H, s), 6.29 (1H, bs), 7.13 (1H, d, J=8.6 Hz), 7.34(2H, d, J=9.0 Hz), 7.63 (2H, d, J=9.0 Hz), 8.17 (1H, dd, J=8.6 Hz, 2.5Hz), 8.53 (1H, d, J=2.5 Hz), 9.77 (1H, bs).

ESI (LC/MS positive mode) m/z 333, 335 (M+H⁺); retention time 2.66 min(Condition 4 for high-performance liquid chromatography).

Example 1-2-6 Production ofN-3-(4-chlorophenyl)-N-1-cyclopropyl-4-methoxy-isophthalamide (Compound1-2-6)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and cyclopropylamine by thesame procedure as in the manufacturing method described in step C ofExample 1-2-3.

ESI (LC/MS positive mode) m/z 345, 347 (M+H⁺); retention time 2.85 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-7 Production ofN-3-(4-chlorophenyl)-4-methoxy-N-1-(1-methoxymethyl-propyl)-isophthalamide

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and 2-amino-1-methoxybutaneby the same procedure as in the manufacturing method described in step Cof Example 1-2-3.

ESI (LC/MS positive mode) m/z 391, 393 (M+H⁺); retention time 3.03 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-8 Production ofN-3-(4-chlorophenyl)-N-1-(2-cyanoethyl)-4-methoxy-isophthalamide(Compound 1-2-8)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and 2-aminopropionitrile bythe same procedure as in the manufacturing method described in step C ofExample 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 2.76 (2H, t, J=6.2 Hz), 3.72 (2H, dd, J=12.5Hz, 6.2 Hz), 4.13 (3H, s), 7.05 (1H, bs), 7.13 (1H, d, J=8.9 Hz), 7.33(2H, d, J=8.9 Hz), 7.60 (2H, d, J=8.9 Hz), 8.13 (1H, dd, J=8.9 Hz, 2.3Hz), 8.61 (1H, d, J=2.3 Hz), 9.71 (1H, bs).

ESI (LC/MS positive mode) m/z 358, 360 (M+H⁺); retention time 2.58 min(Condition 4 for high-performance liquid chromatography).

Example 1-2-9 Production ofN-3-(4-chlorophenyl)-N-1-isopropyl-4-methoxy-isophthalamide (Compound1-2-9)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and isopropylamine by thesame procedure as in the manufacturing method described in step C ofExample 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 1.27 (6H, d, J=6.6 Hz), 3.66 (1H, brs), 4.13(3H, s), 4.20-4.40 (1H, m), 6.16 (1H, brs), 7.13 (1H, d, J=8.9 Hz), 7.34(2H, d, J=8.9 Hz), 7.63 (2H, d, J=8.9 Hz), 8.17 (1H, dd, J=8.9 Hz, 2.3Hz), 8.51 (1H, d, J=2.3 Hz), 9.77 (1H, bs).

ESI (LC/MS positive mode) m/z 401, 403 (M+H⁺); retention time 3.57 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-10 Production ofN-3-(4-chlorophenyl)-4-methoxy-N-1-(3-methyl-butyl)-isophthalamide(Compound 1-2-10)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and 3-methylbutylamine bythe same procedure as in the manufacturing method described in step C ofExample 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 0.95 (6H, d, J=6.3 Hz), 1.51 (2H, dd, J=14.9Hz, 7.0 Hz), 1.64-1.77 (1H, m), 3.47 (2H, dd, J=14.9 Hz, 5.9 Hz), 4.11(3H, s), 6.30 (1H, bs), 7.11 (1H, d, J=8.6 Hz), 7.33 (2H, d, J=8.9 Hz),7.62 (2H, d, J=8.9 Hz), 8.15 (1H, dd, J=8.6 Hz, 2.7 Hz), 8.51 (1H, d,J=2.7 Hz), 9.76 (1H, bs).

ESI (LC/MS positive mode) m/z 375, 377 (M+H⁺); retention time 3.38 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-11 Production ofN-1-benzyl-N-3-(4-chlorophenyl)-4-methoxy-isophthalamide (Compound1-2-11)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and benzylamine by the sameprocedure as in the manufacturing method described in step C of Example1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 4.12 (3H, s), 4.64 (2H, d, J=5.6 Hz), 6.63(1H, bs), 7.13 (1H, d, J=2.3 Hz), 7.30-7.35 (7H, m), 7.60 (2H, d, J=8.9Hz), 8.19 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.55 (1H, d, J=2.3 Hz), 9.73 (1H,bs).

ESI (LC/MS positive mode) m/z 395, 397 (M+H⁺); retention time 3.26 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-12 Production ofN-3-(4-chlorophenyl)-N-1-[2-(1H-imidazol-4-yl)-ethyl]-4-methoxy-isophthalamide(Compound 1-2-12)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and histamine by the sameprocedure as in the manufacturing method described in step C of Example1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 2.89 (2H, t, J=6.2 Hz), 3.70 (2H, dd, J=12.2Hz, 6.2 Hz), 4.08 (3H, s), 6.83 (1H, bs), 7.06 (1H, d, J=8.6 Hz), 7.30(2H, d, J=8.9 Hz), 7.55-7.61 (4H, m), 8.07 (1H, dd, J=8.6 Hz, 2.6 Hz),8.57 (1H, d, J=2.6 Hz), 9.71 (1H, bs).

ESI (LC/MS positive mode) m/z 399, 401 (M+H⁺); retention time 2.14 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-13 Production ofN-3-(4-chlorophenyl)-4-methoxy-N-1-(2-methoxy-ethyl)-isophthalamide(Compound 1-2-13)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and 2-methoxy-ethylamine bythe same procedure as in the manufacturing method described in step C ofExample 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 3.39 (3H, s), 3.56 (2H, dd, J=9.3 Hz, 4.5 Hz),3.66 (2H, dd, J=9.3 Hz, 4.5 Hz), 4.13 (3H, s), 6.65 (1H, bs), 7.13 (1H,d, J=8.8 Hz), 7.34 (2H, d, J=8.9 Hz), 7.63 (2H, d, J=8.9 Hz), 8.16 (1H,dd, J=8.6 Hz, 2.4 Hz), 8.58 (1H, d, J=2.3 Hz), 9.74 (1H, bs).

ESI (LC/MS positive mode) m/z 363, 365 (M+H⁺); retention time 2.57 min(Condition 4 for high-performance liquid chromatography).

Example 1-2-14 Production ofN-1-(2-chloroethyl)-N-3-(4-chlorophenyl)-4-methoxy-isophthalamide(Compound 1-2-14)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and 2-chloro-ethylamine bythe same procedure as in the manufacturing method described in step C ofExample 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 3.70-3.76 (2H, m), 3.77-3.86 (2H, m), 4.13(3H, s), 7.12-7.15 (1H, m), 7.34 (2H, d, J=8.9 Hz), 7.63 (2H, d, J=8.9Hz), 8.14 (1H, dd, J=8.6 Hz, 2.6 Hz), 8.60 (1H, d, J=2.6 Hz), 9.73 (1H,bs).

ESI (LC/MS positive mode) m/z 367, 369 (M+H⁺); retention time 3.01 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-15 Production ofN-3-(4-chlorophenyl)-4-methoxy-N-1-(tetrahydrofuran-2-ylmethyl)-isophthalamide(Compound 1-2-15)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and tetrahydrofurfurylamineby the same procedure as in the manufacturing method described in step Cof Example 1-2-3.

ESI (LC/MS positive mode) m/z 389, 391 (M+H⁺); retention time 2.84 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-16 Production ofN-3-(4-chlorophenyl)-N-1-cyclohexylmethyl-4-methoxy-isophthalamide(Compound 1-2-16)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and aminomethylcyclohexaneby the same procedure as in the manufacturing method described in step Cof Example 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 0.90-1.10 (1H, m), 1.15-1.35 (2H, m),1.50-1.88 (8H, m), 3.30 (2H, t, J=6.3 Hz), 4.13 (3H, s), 6.34 (1H, bs),7.13 (2H, d, J=8.9 Hz), 7.34 (2H, d, J=8.9 Hz), 7.63 (2H, d, J=8.9 Hz),8.17 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.53 (1H, d, J=2.6 Hz), 9.77 (1H, bs).

ESI (LC/MS positive mode) m/z 347, 349 (M+H⁺); retention time 3.01 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-17 Production ofN-3-(4-chlorophenyl)-N-1-furan-2-ylmethyl-4-methoxy-isophthalamide(Compound 1-2-17)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and furfurylamine by thesame procedure as in the manufacturing method described in step C ofExample 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 4.13 (3H, s), 4.64 (2H, d, J=5.3 Hz),6.20-6.33 (1H, m), 6.38 (1H, dd, J=3.0 Hz, 2.0 Hz), 6.60 (1H, bs), 7.13(1H, d, J=8.9 Hz), 7.33 (2H, d, J=8.9 Hz), 7.38 (1H, dd, J=1.8 Hz, 0.8Hz), 7.61 (2H, d, J=8.9 Hz), 8.18 (1H, dd, J=8.9 Hz, 2.4 Hz), 8.55 (1H,d, J=2.4 Hz), 9.74 (1H, bs).

ESI (LC/MS positive mode) m/z 385, 387 (M+H⁺); retention time 3.08 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-18 Production ofN-3-(4-chlorophenyl)-N-1-[2-(2-hydroxyethoxy)-ethyl]-4-methoxy-isophthalamide(Compound 1-2-18)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid and2-(2-aminoethoxy)ethanol by the same procedure as in the manufacturingmethod described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 393, 395 (M+H⁺); retention time 2.44 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-19 Production ofN-3-(4-chlorophenyl)-N-1-(2-dimethylaminoethyl)-4-methoxy-isophthalamide(Compound 1-2-19)

The captioned compound was synthesized usingN-(4-chlorophenyl)-4-methoxyisophthalic acid andN,N-dimethylethylenediamine by the same procedure as in themanufacturing method described in step C of Example 1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 2.51 (2H, t, J=5.5 Hz), 3.53 (2H, dd, J=11.2Hz, 5.5 Hz), 4.12 (3H, s), 6.89 (1H, bs), 7.12 (1H, d, J=8.6 Hz), 7.33(2H, d, J=8.9 Hz), 7.63 (2H, d, J=8.9 Hz), 8.15 (1H, dd, J=8.6 Hz, 2.3Hz), 8.58 (1H, d, J=2.3 Hz), 9.74 (1H, bs).

ESI (LC/MS positive mode) m/z 376, 378 (M+H⁺); retention time 2.63 min(Condition 3 for high-performance liquid chromatography).

Example 1-2-20 Production of 4-nitro-3-N-(4-chlorophenyl)-isophthalamide(Compound 1-2-20)

Step A: Preparation of methyl N-(4-chlorophenyl)-4-nitroisophthamate

5-(Methoxycarbonyl)-2-nitrobenzoic acid (CAS registry number:76143-33-4) (1.50 g) and 0.05 mL of N,N-dimethylformamide were dissolvedin 150 mL of dichloromethane, and the solution was cooled to 0° C. Tothis solution, 0.87 mL of oxalyl chloride was added little by little,and the mixture was stirred for 30 minutes at 0° C., followed bystirring the mixture for 13 hours at room temperature. The reactionmixture was distilled under reduced pressure, and dried to obtain alight yellow solid, which was dissolved in 150 mL of dichloromethane. Tothis solution, a solution of 0.94 g of 4-chloroaniline and 3.57 mL ofN,N-diisopropylethylamine dissolved in 25 mL of dichloromethane wasadded little by little. The mixture was stirred for 2 hours and a halfat room temperature, whereafter 100 mL of a saturated aqueous solutionof ammonium chloride was added to separate the organic layer. Theaqueous layer was extracted twice with 50 mL of dichloromethane. Therespective organic layers were combined, whereafter the combined organiclayer was washed with 50 mL of a saturated aqueous solution of sodiumchloride, and dried over anhydrous sodium sulfate. The anhydrous sodiumsulfate was separated by filtration, and washed with dichloromethane.The filtrate and the washings were combined, and dichloromethane wasdistilled off under reduced pressure. The resulting residue was purifiedby silica gel column chromatography. The resulting solid was dried underreduced pressure to obtain 1.82 g (81%) of methylN-(4-chlorophenyl)-4-nitroisophthalamate.

¹H-NMR (270 MHz, CDCl₃) δ 4.00 (3H, s), 7.36 (2H, d, J=8.9 Hz), 7.55(2H, d, J=8.9 Hz), 7.66 (1H, bs), 8.14 (1H, d, J=8.6 Hz), 8.25-8.29 (2H,m).

EI (positive mode) m/z 334 (M⁺).

Step B: Preparation of 4-nitro-3-N-(4-chlorophenyl)-isophthalamide

Methyl N-(4-chlorophenyl)-4-nitroisophthalamate (220 mg) obtained instep A was dissolved in 10 mL of a methanol solution of 7 mols ofammonia. After the reactor was sealed, the solution was heated for 36hours at 80° C. with stirring. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography. The resulting solid was dried under reducedpressure to obtain 48 mg (23%) of4-nitro-3-N-(4-chlorophenyl)-isophthalamide.

¹H-NMR (270 MHz, DMSO-d₆) δ 7.45 (2H, d, J=8.9 Hz), 7.72 (2H, d, J=8.9Hz), 7.83 (1H, bs), 8.16-8.26 (3H, m), 8.39 (1H, bs), 11.00 (1H, bs).

ESI (LC/MS positive mode) m/z 320, 322 (M+H⁺); retention time 3.00 min(Condition 1 for high-performance liquid chromatography).

Example 1-2-21 Production of 4-amino-3-N-(4-chlorophenyl)-isophthalamide(Compound 1-2-21)

4-Nitro-3-N-(4-chlorophenyl)-isophthalamide (46 mg) obtained in Example1-2-20 was dissolved in 7 mL of methanol, and 10 mg of platinum oxidewas added to the solution, followed by stirring the mixture for 30minutes at room temperature in an atmosphere of hydrogen. The reactionmixture was filtered to remove insolubles, and the filtrate wasconcentrated under reduced pressure. The resulting solid was dried underreduced pressure to obtain 41 mg (99%) of4-amino-3-N-(4-chlorophenyl)-isophthalamide.

¹H-NMR (270 MHz, DMSO-d₆) δ 6.73-6.76 (3H, m), 7.07 (1H, bs), 7.41 (2H,d, J=8.9 Hz), 7.64 (1H, bs), 7.51-7.76 (3H, m), 8.17 (1H, d, J=2.0 Hz),10.24 (1H, bs).

ESI (LC/MS positive mode) m/z 290, 292 (M+H⁺); retention time 2.78 min(Condition 1 for high-performance liquid chromatography).

Example 1-2-22 Production of4-chloro-3-N-(4-chlorophenyl)-isophthalamide (Compound 1-2-22)

4-Amino-3-N-(4-chlorophenyl)-isophthalamide (25 mg) obtained in Example1-2-21 was dissolved in a solvent mixture of 2 mL of tetrahydrofuran,1.5 mL of acetic acid, and 0.5 mL of purified water, and 12 mg of sodiumnitrite was added to the solution. The reaction mixture was stirred for30 minutes at room temperature, then 100 mg of cuprous chloride wasadded, and the mixture was further stirred for 15 hours at 70° C. Asaturated aqueous solution of sodium bicarbonate (20 mL) was added, andthe mixture was extracted twice with 50 mL of ethyl acetate. Therespective organic layers were combined, whereafter the combined organiclayer was washed with 20 mL of a saturated aqueous solution of sodiumchloride, and dried over anhydrous sodium sulfate. The anhydrous sodiumsulfate was separated by filtration, and washed with ethyl acetate. Thefiltrate and the washings were combined, and ethyl acetate was distilledoff under reduced pressure. The resulting residue was purified using amicromass spectrometer (ZMD produced by Micromass) equipped with agradient high-performance liquid chromatograph 996-600E produced byWaters. The resulting solid was dried under reduced pressure to obtain11 mg (41%) of 4-chloro-3-N-(4-chlorophenyl)-isophthalamide.

¹H-NMR (270 MHz, CD₃OD) δ 7.37 (2H, d, J=8.9 Hz), 7.63 (1H, d, J=8.2Hz), 7.69 (2H, d, J=8.9 Hz), 7.97 (1H, dd, J=8.2 Hz, 2.3 Hz), 8.07 (1H,d, J=2.3 Hz).

ESI (LC/MS positive mode) 309, 311 (M+H⁺); retention time 3.04 min(Condition 1 for high-performance liquid chromatography).

Example 1-2-23 Production of 4-bromo-3-N-(4-chlorophenyl)-isophthalamide(Compound 1-2-23)

The captioned compound was synthesized from4-amino-3-N-(4-chlorophenyl)-isophthalamide and cuprous bromide by thesame procedure as in the manufacturing method described in Example1-1-22.

¹H-NMR (270 MHz, CD₃OD) δ 7.37 (2H, d, J=8.8 Hz), 7.68 (2H, d, J=8.8Hz), 7.80 (1H, d, J=8.2 Hz), 7.88 (1H, d, J=8.2 Hz), 8.02 (1H, bs).

ESI (LC/MS positive mode) m/z 353, 355 (M+H⁺); retention time 3.00 min(Condition 1 for high-performance liquid chromatography).

Example 1-2-24 Production ofN³-(4-bromo-2-chloro-phenyl)-N¹-(2-hydroxy-1-methyl-ethyl)-4-methoxy-isophthalamide(Compound 1-2-24)

The captioned compound was synthesized usingN-(2-chloro-4-bromophenyl)-4-methoxyisophthalic acid and(±)-2-amino-1-propanol by the same procedure as in the manufacturingmethod described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 441, 443, 445 (M+H⁺); retention time 3.36min (Condition 1 for high-performance liquid chromatography).

Example 1-2-25 Production ofN³-(4-bromo-2-chloro-phenyl)-N¹—((S)-1-hydroxymethyl-2-methyl-propyl)-4-methoxy-isophthalamide(Compound 1-2-25)

The captioned compound was synthesized usingN-(2-chloro-4-bromophenyl)-4-methoxyisophthalic acid and(S)-(+)-2-amino-3-methylbutanol by the same procedure as in themanufacturing method described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 469, 471, 473 (M+H⁺); retention time 3.67min (Condition 1 for high-performance liquid chromatography).

Example 1-3-1 Production of3-N-(4-bromo-2-fluorophenyl)-4-methoxy-isophthalamide (Compound 1-3-1)

Step A: Preparation of methyl 5-cyano-2-methoxybenzoate (CAS RegistryNumber: 40757-12-8)

Methyl 5-bromo-2-methoxybenzoate (29.3 g) obtained in step A of Example1-1-1, and 33.1 g of zinc cyanide were dissolved in 650 mL ofN,N-dimethylformamide. N,N-Dimethylformamide was degassed under reducedpressure, and then the interior of the reactor was purged with nitrogen.After 9.8 g of tetrakistriphenylphosphine palladium was added,N,N-dimethylformamide was deaerated again under reduced pressure, andthen the interior of the reactor was purged with argon. This solutionwas stirred for 2 hours at 100° C., whereafter the solvent was distilledoff under reduced pressure, and the residue was dissolved in ethylacetate. The insolubles were removed by filtration, and washed withethyl acetate. The filtrate and the washings were combined, water wasadded, and then the organic layer was separated. The aqueous layer wasextracted twice with ethyl acetate. After the respective organic layerswere combined, the combined organic layer was washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous sodiumsulfate. The anhydrous sodium sulfate was separated by filtration, andthen washed with ethyl acetate. The filtrate and the washings werecombined, and ethyl acetate was distilled off under reduced pressure.The resulting residue was washed with diethyl ether. The resulting solidwas dried under reduced pressure to obtain 13.5 g (42%) of methyl5-cyano-2-methoxybenzoate. The mother liquor and the washings werecombined, and concentrated, whereafter the residue was recrystallizedfrom t-butyl methyl ether. The resulting crystals were separated byfiltration, then washed with a 1:1 solvent mixture of n-hexane anddiethyl ether, and then dried under reduced pressure to obtain 4.6 g(14%) of methyl 5-cyano-2-methoxybenzoate.

¹H-NMR (400 MHz, CDCl₃) δ 3.92 (3H, s), 3.98 (3H, s), 7.06 (1H, d, J=8.6Hz), 7.76 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.11 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 192 (M+H⁺); retention time 2.56 min(Condition 1 for high-performance liquid chromatography).

Step B: Preparation of 6-methoxyisophthalamic acid (CAS Registry Number:89366-41-6)

Methyl 5-cyano-2-methoxybenzoate (2 g) prepared in step A was dissolvedin 24 mL of dimethyl sulfoxide, and 12 mL of a 1 M aqueous solution ofsodium hydroxide was added. After stirring for 4 hours and a half at 80°C., the mixture was cooled in an ice bath, and adjusted to pH of about 4with the use of 10 mL of 1 M hydrochloric acid. The resulting solutionwas diluted with 200 mL of water, and cooled for several hours in arefrigerator. The precipitate formed was separated by filtration, washedwith cold water, and then dried over diphosphorus pentoxide underreduced pressure to obtain 1.3 g (63%) of 6-methoxyisophthalamic acid.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.89 (3H, s), 7.18 (1H, d, J=8.6 Hz), 7.28(1H, bs), 7.97 (1H, bs), 8.02 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.18 (1H, d,J=2.3 Hz), 12.80 (1H, s).

ESI (LC/MS positive mode) m/z 196 (M+H⁺); retention time 0.55 min(Condition 1 for high-performance liquid chromatography).

Step C: Preparation of3-N-(4-bromo-2-fluorophenyl)-4-methoxyisophthalamide (Compound 1-3-1)

To 202 mg (1.24 mmols/g) ofN-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene(PS-carbodiimide), there were added 0.5 mL (0.25 mol) of anN,N-dimethylformamide solution of 6-methoxyisophthalamic acid preparedin step B, 0.75 mL (0.25M) of an N,N-dimethylformamide solution ofbenzotriazol-1-ol monohydrate, and 20 mg of 4-bromo-2-fluoroaniline.This mixture was agitated for 16 hours at room temperature, and thenagitated for 24 hours at 60° C. To the mixture, 213 mg (2.64 mmols/g) ofmacroporous triethylammonium methylpolystyrene carbonate (MP-carbonate)and 0.5 mL of N,N-dimethylformamide were added, followed by agitatingthe mixture for 12 hours at room temperature. The polystyrene solidphase-carried reagent was separated by filtration, and washed withN,N-dimethylformamide, tetrahydrofuran, and dichloromethane in thisorder. Then, the filtrate and the washings were combined, andconcentrated. The resulting residue was purified using a micromassspectrometer (ZMD produced by Micromass) equipped with a gradienthigh-performance liquid chromatograph 996-600E produced by Waters,thereby obtaining 9 mg (22%) of3-N-(4-bromo-2-fluorophenyl)-4-methoxyisophthalamide.

ESI (LC/MS positive mode) m/z 367, 369 (M+H⁺); retention time 3.14 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-2 Production of3-N-(2,3-dichlorophenyl)-4-methoxyisophthalamide (Compound 1-3-2)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2,3-dichloroaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 339, 341, 343 (M+H⁺); retention time 3.24min (Condition 1 for high-performance liquid chromatography).

Example 1-3-3 Production of3-N-(4-chloro-2,5-dimethoxyphenyl)-4-methoxyisophthalamide (Compound1-3-3)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 4-chloro-2,5-dimethoxyaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 365, 367 (M+H⁺); retention time 3.09 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-4 Production ofN-3-(2-chloro-4-methylphenyl)-4-methoxyisophthalamide (Compound 1-3-4)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-chloro-4-methylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 319, 321 (M+H⁺); retention time 3.23 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-5 Production of4-methoxy-3-N-(2-trifluoromethoxyphenyl)-isophthalamide (Compound 1-3-5)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-trifluoromethoxyaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 355 (M+H⁺); retention time 3.22 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-6 Production of4-methoxy-3-N-(5,6,7,8-tetrahydronaphthalen-1-yl)isophthalamide(Compound 1-3-6)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 1-amino-5,6,7,8-tetrahydronaphthalene by the same procedure as inthe manufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 325 (M+H⁺); retention time 3.21 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-7 Production of 3-N-(2-chlorophenyl)-4-methoxyisophthalamide(Compound 1-3-7)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-chloroaniline by the same procedure as in the manufacturing methoddescribed in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 305, 307 (M+H⁺); retention time 2.95 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-8 Production of3-N-(2-fluoro-3-trifluoromethylphenyl)-4-methoxyisophthalamide (Compound1-3-8)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-fluoro-3-trifluoromethylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 357 (M+H⁺); retention time 3.19 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-9 Production of 3-N-indan-5-yl-4-methoxyisophthalamide(Compound 1-3-9)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand indan-4-yl-amine by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 311 (M+H⁺); retention time 3.10 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-10 Production of4-methoxy-3-N-(2-methoxyphenyl)isophthalamide (Compound 1-3-10)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-methoxyaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 301 (M+H⁺); retention time 3.53 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-11 Production of3-N-(3-chloro-4-methylphenyl)-4-methoxyisophthalamide (Compound 1-3-11)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 3-chloro-4-methylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 319, 321 (M+H⁺); retention time 3.98 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-12 Production of3-N-(2-fluorophenyl)-4-methoxyisophthalamide (Compound 1-3-12)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-fluoroaniline by the same procedure as in the manufacturing methoddescribed in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 289 (M+H⁺); retention time 2.73 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-13 Production of3-N-(2-acetylphenyl)-4-methoxyisophthalamide (Compound 1-3-13)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-acetylaniline by the same procedure as in the manufacturing methoddescribed in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 313 (M+H⁺); retention time 2.80 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-14 Production of 3-N-(4-bromophenyl)-4-methoxyisophthalamide(Compound 1-3-14)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 4-bromoaniline by the same procedure as in the manufacturing methoddescribed in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 349, 351 (M+H⁺); retention time 2.95 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-15 [Production of4-methoxy-3-N-(2-methylsulfanylphenyl)isophthalamide (Compound 1-3-15)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand (2-amino)phenylmethylsulfide by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 317 (M+H⁺); retention time 3.02 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-16 Production of3-N-(2-chloro-5-trifluoromethylphenyl)-4-methoxyisophthalamide (Compound1-3-16)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-chloro-5-trifluoromethylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 373, 375 (M+H⁺); retention time 3.30 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-17 Production of3-N-(2-chloro-4-fluoro-5-methylphenyl)-4-methoxyisophthalamide (Compound1-3-17)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-chloro-4-fluoro-5-methylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 337, 339 (M+H⁺); retention time 3.21 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-18 Production of3-N-(3,5-dimethoxyphenyl)-4-methoxyisophthalamide (Compound 1-3-18)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 3,5-dimethoxyaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 331 (M+H⁺); retention time 3.43 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-19 Production of4-methoxy-3-N-(4-phenoxyphenyl)-isophthalamide (Compound 1-3-19)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 4-phenoxyaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 363 (M+H⁺); retention time 3.31 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-20 Production of3-N-(3,4-dimethylphenyl)-4-methoxyisophthalamide (Compound 1-3-20)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 3,4-dimethylaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 299 (M+H⁺); retention time 3.01 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-21 Production of4-methoxy-3-N-(4-trifluoromethylphenyl)isophthalamide (Compound 1-3-21)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 4-trifluoromethylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 339 (M+H⁺); retention time 3.09 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-22 Production of3-N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-methoxyisophthalamide (Compound1-3-22)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2,3-dihydrobenzo[1,4]dioxin-6-ylamine by the same procedure as inthe manufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 329 (M+H⁺); retention time 2.60 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-23 Production of 4-methoxy-3-N-o-tolylisophthalamide(Compound 1-3-23)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-methylaniline by the same procedure as in the manufacturing methoddescribed in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 285 (M+H⁺); retention time 3.49 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-24

Production of 3-N-(2,4-difluorophenyl)-4-methoxyisophthalamide (Compound1-3-24)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2,4-difluoroaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 307 (M+H⁺); retention time 2.79 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-25 Production of3-N-(3-ethynylphenyl)-4-methoxyisophthalamide (Compound 1-3-25)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 3-ethynylaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 295 (M+H⁺); retention time 2.89 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-26 Production of4-methoxy-3-N-(3-trifluoromethylphenyl)-isophthalamide (Compound 1-3-26)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 3-trifluoromethylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 339 (M+H⁺); retention time 3.05 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-27 Production of3-N-(3-chlorophenyl)-4-methoxy-isophthalamide (Compound 1-3-27)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 3-chloroaniline by the same procedure as in the manufacturing methoddescribed in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 305, 307 (M+H⁺); retention time 2.90 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-28 Production of3-N-(2-fluoro-5-trifluoromethylphenyl)-4-methoxyisophthalamide (Compound1-3-28)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-fluoro-5-trifluoromethylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 357 (M+H⁺); retention time 3.19 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-29 Production of3-N-(2,5-dimethoxyphenyl)-4-methoxyisophthalamide (Compound 1-3-29)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2,5-dimethoxyaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 331 (M+H⁺); retention time 2.89 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-30 Production of4-(5-carbamoyl-2-methoxybenzoylamino)benzoic acid ethyl ester (Compound1-3-30)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand ethyl 4-amino-benzoate by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) m/z 343 (M+H⁺); retention time 2.92 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-31 Production of3-N-(5-chloro-pyridin-2-yl)-4-methoxyisophthalamide (Compound 1-3-31)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-amino-5-chloro-pyridine by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 306, 308 (M+H⁺); retention time 2.77 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-32 Production of 4-methoxy-3-N-(4-tolyl)isophthalamide(Compound 1-3-32)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 4-methylaniline by the same procedure as in the manufacturing methoddescribed in step C of Example 1-3-1.

ESI (LC/MS positive mode) 285 (M+H⁺); retention time 2.77 min (Condition1 for high-performance liquid chromatography).

Example 1-3-33 Production of4-methoxy-3-N-(5-methoxy-2-methylphenyl)isophthalamide (Compound 1-3-33)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 5-methoxy-2-methylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 315 (M+H⁺); retention time 2.79 min (Condition1 for high-performance liquid chromatography).

Example 1-3-34 Production of4-methoxy-3-N-(3-methoxy-5-trifluoromethylphenyl)isophthalamide(Compound 1-3-34)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 3-methoxy-5-trifluoromethylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 369 (M+H⁺); retention time 3.17 min (Condition1 for high-performance liquid chromatography).

Example 1-3-35 Production of3-N-(2,4-dimethoxyphenyl)-4-methoxyisophthalamide (Compound 1-3-35)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2,4-dimethoxyaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 331 (M+H⁺); retention time 2.77 min (Condition1 for high-performance liquid chromatography).

Example 1-3-36 Production of3-N-(2-chloro-5-methylphenyl)-4-methoxyisophthalamide (Compound 1-3-36)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-chloro-5-methylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 319, 321 (M+H⁺); retention time 3.18 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-37 Production of3-N-(2-chloro-5-methylphenyl)-4-methoxyisophthalamide (Compound 1-3-37)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-chloro-5-methoxyaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 335, 337 (M+H⁺); retention time 3.06 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-38 Production of4-methoxy-3-N-naphthalen-1-yl-isophthalamide (Compound 1-3-38)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 1-naphthaleneamine by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 321 (M+H⁺); retention time 2.90 min (Condition1 for high-performance liquid chromatography).

Example 1-3-39 Production of 4-methoxy-3-N-quinolin-5-yl-isophthalamide(Compound 1-3-39)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 5-aminoquinoline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 322 (M+H⁺); retention time 2.93 min (Condition5 for high-performance liquid chromatography).

Example 1-3-40 Production of 3-N-(1H-indol-5-yl)-4-methoxyisophthalamide(Compound 1-3-40)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 5-aminoindole by the same procedure as in the manufacturing methoddescribed in step C of Example 1-3-1.

ESI (LC/MS positive mode) 310 (M+H⁺); retention time 2.44 min (Condition1 for high-performance liquid chromatography).

Example 1-3-41 Production of3-N-(4-bromo-2-chlorophenyl)-4-methoxyisophthalamide (Compound 1-3-41)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 4-bromo-2-chloroaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 383, 385, 387 (M+H⁺); retention time 3.39 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-42 Production of3-N-(2-bromo-4-chlorophenyl)-4-methoxyisophthalamide (Compound 1-3-42)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-bromo-4-chloroaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 383, 385, 387 (M+H⁺); retention time 3.36 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-43 Production of3-N-(2-chloro-4-trifluoromethylphenyl)-4-methoxyisophthalamide (Compound1-3-43)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-chloro-4-trifluoromethylaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 373, 375 (M+H⁺); retention time 3.47 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-44 Production of3-N-(4-chloro-2-fluorophenyl)-4-methoxyisophthalamide (Compound 1-3-44)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 4-chloro-2-fluoroaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 323, 325 (M+H⁺); retention time 3.09 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-45 Production of3-N-(2,4-dibromophenyl)-4-methoxyisophthalamide (Compound 1-3-45)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2,4-dibromoaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 427, 429, 431 (M+H⁺); retention time 3.42 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-46 Production of3-N-(2,4-dichlorophenyl)-4-methoxyisophthalamide (Compound 1-3-46)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2,4-dichloroaniline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 339, 341, 343 (M+H⁺); retention time 3.32 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-47 Production of4-methoxy-3-N-naphthalen-2-yl-isophthalamide (Compound 1-3-47)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-naphthaleneamine by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 321 (M+H⁺); retention time 3.10 min (Condition1 for high-performance liquid chromatography).

Example 1-3-48 Production of3-N-(2-bromo-4-trifluoromethoxyphenyl)-4-methoxyisophthalamide (Compound1-3-48)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-bromo-4-trifluoromethoxyaniline by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 433, 435 (M+H⁺); retention time 3.62 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-49 Production of3-N-(5-bromo-pyridin-2-yl)-4-methoxy-isophthalamide (Compound 1-3-49)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-amino-5-bromopyridine by the same procedure as in themanufacturing method described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 350, 352 (M+H⁺); retention time 2.86 min(Condition 1 for high-performance liquid chromatography).

Example 1-3-50 Production of 4-methoxy-3-N-quinolin-2-yl-isophthalamide(Compound 1-3-50)

The captioned compound was synthesized from 6-methoxyisophthalamic acidand 2-aminoquinoline by the same procedure as in the manufacturingmethod described in step C of Example 1-3-1.

ESI (LC/MS positive mode) 322 (M+H⁺); retention time 2.42 min (Condition1 for high-performance liquid chromatography).

Example 1-4-1 Production of3-N-(4-trifluoromethoxy-2-chlorophenyl)-4-methoxyisophthalamide(Compound 1-4-1)

Step A: Preparation of 5-cyano-2-methoxybenzoic acid (CAS RegistryNumber: 84923-71-7)

Methyl 5-cyano-2-methoxybenzoate (2 g) obtained in step A of Example1-3-1 was dissolved in 28 mL of 1,4-dioxane, and 21 mL of an aqueoussolution of 2.5 mols of sodium hydroxide was added. After stirring for30 minutes at room temperature, the reaction mixture was cooled in anice bath, and neutralized with the use of 50 mL of 1 M hydrochloricacid. The resulting aqueous solution was extracted 6 times withmethylene chloride. The respective organic layers were combined,whereafter the combined organic layer was washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous sodiumsulfate. The anhydrous sodium sulfate was separated by filtration, andwashed with methylene chloride. The filtrate and the washings werecombined, and methylene chloride was distilled off under reducedpressure. The resulting solid was dried under reduced pressure to obtain1.6 g (87%) of 5-cyano-2-methoxybenzoic acid.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.91 (3H, s), 7.32 (1H, d, J=8.8 Hz), 7.98(1H, dd, J=8.8 Hz, 2.0 Hz), 8.02 (1H, d, J=2.0 Hz), 13.15 (1H, s).

ESI (LC/MS positive mode) m/z 178 (M+H⁺); retention time 1.94 min(Condition 1 for high-performance liquid chromatography).

Step B: Preparation of5-cyano-N-(4-trifluoromethoxy-2-chlorophenyl)-2-methoxybenzamide

5-Cyano-2-methoxybenzoic acid (0.73 g) obtained in step A, and 16 μL ofN,N-dimethylformamide were dissolved in 18 mL of dichloromethane, andthe solution was cooled to 0° C. To this solution, 0.54 mL of oxalylchloride was added little by little, and the mixture was stirred for 2.7hours at room temperature. The reaction mixture was distilled underreduced pressure, and dried to obtain a light yellow solid. This solidwas added, with the use of 10 mL of tetrahydrofuran, to a solution of0.95 g of 4-trifluoromethoxy-2-chloroaniline and 2.1 mL ofN,N-diisopropylethylamine dissolved in 20 mL of tetrahydrofuran. Themixture was stirred overnight at room temperature, and thentetrahydrofuran was distilled off under reduced pressure. The resultingsolid was purified by silica gel column chromatography using methylenechloride as an elution solvent, thereby obtaining 1.37 g (90%) of5-cyano-N-(4-trifluoromethoxy-2-chlorophenyl)-2-methoxybenzamide.

¹H-NMR (400 MHz, DMSO-d₆) δ 4.13 (3H, s), 7.48 (2H, d, J=8.8 Hz), 7.75(1H, d, J=2.1 Hz), 8.09 (1H, dd, J=8.8 Hz, 2.1 Hz), 8.30 (1H, s), 8.37(1H, d, J=8.8 Hz), 10.41 (1H, s).

ESI (LC/MS positive mode) m/z 371, 373 (M+H⁺); retention time 3.54 min(Condition 2 for high-performance liquid chromatography).

Step C: Preparation of3-N-(4-trifluoromethoxy-2-chlorophenyl)-4-methoxyisophthalamide

The captioned compound was synthesized from5-cyano-N-(4-trifluoromethoxy-2-chlorophenyl)-2-methoxybenzamideobtained in step B by the same procedure as in step E of Example 1-1-1.

¹H-NMR (400 MHz, CD₃OD) δ 4.19 (3H, s), 7.33 (1H, d, J=8.8 Hz), 7.35(1H, d, J=8.8 Hz), 7.50 (1H, s), 8.12 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.64(1H, d, J=8.8 Hz), 8.72 (1H, d, J=2.4 Hz).

ESI (LC/MS positive mode) m/z 389, 391 (M+H⁺); retention time 3.46 min(Condition 1 for high-performance liquid chromatography).

Example 1-4-2 Production of3-N-(2-bromo-4-trifluoromethyl-phenyl)-4-methoxy-isophthalamide(Compound 1-4-2)

The captioned compound was synthesized from 5-cyano-2-methoxybenzoicacid and 2-bromo-4-trifluoromethylaniline by the same procedure as inthe manufacturing method described in steps B and C of Example 1-4-1.

ESI (LC/MS positive mode) 417, 419 (M+H⁺); retention time 3.52 min(Condition 1 for high-performance liquid chromatography).

Example 1-4-3 Production of4-methoxy-3-N-(5-trifluoromethyl-pyridin-2-yl)-isophthalamide (Compound1-4-3)

The captioned compound was synthesized from 5-cyano-2-methoxybenzoicacid and 2-amino-5-trifluoromethylpyridine by the same procedure as inthe manufacturing method described in steps B and C of Example 1-4-1.

ESI (LC/MS positive mode) 340 (M+H⁺); retention time 3.02 min (Condition1 for high-performance liquid chromatography).

Example 1-4-4 Production of3-N-(3-bromo-pyridin-4-yl)-4-methoxy-isophthalamide (Compound 1-4-4)

The captioned compound was synthesized from 5-cyano-2-methoxybenzoicacid and 4-amino-3-bromopyridine by the same procedure as in themanufacturing method described in steps B and C of Example 1-4-1.

ESI (LC/MS positive mode) 350, 352 (M+H⁺); retention time 2.03 min(Condition 1 for high-performance liquid chromatography).

Example 1-4-5 Production of3-N-(2,6-dimethoxy-pyridin-3-yl)-4-methoxyisophthalamide (Compound1-4-5)

The captioned compound was synthesized from 5-cyano-2-methoxybenzoicacid and 3-amino-2,6-dimethoxypyridine by the same procedure as in themanufacturing method described in steps B and C of Example 1-4-1.

ESI (LC/MS positive mode) 332 (M+H⁺); retention time 2.94 min (Condition1 for high-performance liquid chromatography).

Example 1-4-6 Production of N-benzothiazol-2-yl-4-methoxyisophthalamide(Compound 1-4-6)

The captioned compound was synthesized from 5-cyano-2-methoxybenzoicacid and 2-aminobenzothiazole by the same procedure as in themanufacturing method described in steps B and C of Example 1-4-1.

ESI (LC/MS positive mode) m/z 328 (M+H⁺); retention time 2.77 min(Condition 1 for high-performance liquid chromatography).

Example 1-4-7 Production ofN-(2-acetylthiophen-3-yl)-4-methoxyisophthalamide (Compound 1-4-7)

The captioned compound was synthesized from 5-cyano-2-methoxybenzoicacid and 2-acetyl-3-aminothiophene by the same procedure as in themanufacturing method described in steps B and C of Example 1-4-1.

ESI (LC/MS positive mode) m/z 319 (M+H⁺); retention time 2.70 min(Condition 1 for high-performance liquid chromatography).

Example 2-1-1 Production of4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide (Compound2-1-1)

Step A: Preparation of4-bromo-1-methoxy-2-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzene

60% Oil-suspended sodium hydride (20.5 mg) was washed with n-hexane, andthen suspended in 2 mL of tetrahydrofuran. To this suspension, 0.13 mLof diethyl (4-trifluoromethoxybenzyl)phosphonate was added in a streamof nitrogen while cooled with ice, and then the mixture was heated for 5minutes under reflux. This mixture was cooled again in an ice bath, and0.1 g of 5-bromo-2-methoxybenzaldehyde (CAS registry number: 25016-01-7)was added. The reaction mixture was stirred for 6 hours at roomtemperature, then poured into water, and extracted with ethyl acetate 3times. The respective organic layers were combined, whereafter thecombined organic layer was washed with a saturated aqueous solution ofsodium chloride, and dried over anhydrous sodium sulfate. The anhydroussodium sulfate was separated by filtration, and washed with ethylacetate. The filtrate and the washings were combined, and ethyl acetatewas distilled off under reduced pressure. The residue was purified bycolumn chromatography (5 g silica gel) using a 1:10 mixture of ethylacetate and n-hexane as an elution solvent, thereby obtaining 152 mg(88%) of4-bromo-1-methoxy-2-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzene.

¹H-NMR (400 MHz, CDCl₃) δ 3.87 (3H, s), 6.77 (1H, d, J=8.8 Hz), 7.05(1H, d, J=16.1 Hz), 7.19 (2H, d, J=8.3 Hz), 7.34 (1H, d, J=16.1 Hz),7.34 (1H, dd, J=8.6 Hz, 2.4 Hz), 7.52 (2H, d, J=8.8 Hz), 7.67 (1H, d,J=2.4 Hz).

EIMS m/z 372, 374 (M⁺).

Step B: Preparation of4-methoxy-3-[(E)-2-(4-trifluoromethoxy-phenyl)vinyl]benzonitrile

The captioned compound was synthesized from4-bromo-1-methoxy-2-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzeneobtained in step A in accordance with the same procedure as in themethods described in step D of Example 1-1-1.

¹H-NMR (400 MHz, CDCl₃) δ 3.95 (3H, s), 6.94 (1H, d, J=8.8 Hz), 7.09(1H, d, J=16.6 Hz), 7.21 (2H, d, J=8.8 Hz), 7.33 (1H, d, J=16.6 Hz),7.54 (2H, d, J=8.8 Hz), 7.55 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.83 (1H, d,J=2.0 Hz).

EIMS m/z 319 (M⁺).

Step C: Preparation of4-methoxy-3-[(E)-2-(4-trifluoromethoxy-phenyl)vinyl]benzamide (Compound2-1-1)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxy-phenyl)vinyl]benzonitrileobtained in step B in accordance with the same procedure as in themethods described in step E of Example 1-1-1.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.92 (3H, s), 6.93 (1H, d, J=8.8 Hz), 7.17(1H, d, J=16.6 Hz), 7.20 (2H, d, J=8.5 Hz), 7.41 (1H, d, J=16.6 Hz),7.55 (2H, d, J=8.8 Hz), 7.70 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.09 (1H, d,J=2.4 Hz).

ESI (LC/MS positive mode) m/z 338 (M+H⁺); retention time 2.91 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-1

Production ofN-cyclopentyl-4-methoxy-3-[(E)-2-(4-trifluoromethoxy-phenyl)vinyl]benzamide(Compound 2-2-1)

Step A: Preparation of ethyl4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoate

60% Oil-suspended sodium hydride (0.7 g) was washed with n-hexane, andthen suspended in 48 mL of tetrahydrofuran. To this suspension, 5.78 gof diethyl (4-trifluoromethoxybenzyl)phosphonate was added in a streamof nitrogen while cooled with ice, and then the mixture was heated for 5minutes under reflux. This mixture was cooled again in an ice bath, and3.5 g of ethyl 3-formyl-4-methoxybenzoate obtained in Step C of Example1-2-1 was added. The reaction mixture was stirred overnight at roomtemperature, then poured into water, and extracted with ethyl acetate 3times. The respective organic layers were combined, whereafter thecombined organic layer was washed with a saturated aqueous solution ofsodium chloride, and dried over anhydrous sodium sulfate. The anhydroussodium sulfate was separated by filtration, and washed with ethylacetate. The filtrate and the washings were combined, and ethyl acetatewas distilled off under reduced pressure. The residue was purified bycolumn chromatography (100 g silica gel) using a 20:1 mixture of ethylacetate and n-hexane as an elution solvent, thereby obtaining 5.5 g(90%) of ethyl4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoate.

¹H-NMR (400 MHz, CDCl₃) δ 1.41 (3H, t, J=7.1 Hz), 3.95 (3H, s), 4.39(2H, q, J=7.1 Hz), 6.79 (1H, d, J=8.6 Hz), 7.17 (1H, d, J=16.6 Hz), 7.20(2H, d, J=8.8 Hz), 7.41 (1H, d, J=16.6 Hz), 7.56 (2H, d, J=8.8 Hz), 7.97(1H, dd, J=8.6 Hz, 2.4 Hz), 8.27 (1H, d, J=2.4 Hz).

ESI (LC/MS positive mode) m/z 367 (M+H⁺); retention time 4.21 min(Condition 2 for high-performance liquid chromatography).

Step B: Preparation of4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid

Ethyl 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoate (4.5g) obtained in step A was dissolved in 40 mL of methanol, and 16 mL of a20% aqueous solution of potassium hydroxide was added. The resultingsolution was stirred for 2 hours at 80° C., and then cooled to roomtemperature. The reaction mixture was adjusted to pH of about 3 with theuse of 60 mL of 1 M hydrochloric acid. The resulting precipitate wasseparated by filtration, washed with water, and then dried overdiphosphorus pentoxide under reduced pressure to obtain 4.1 g (99%) of4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid.

¹H-NMR (400 MHz, CDCl₃) δ 3.98 (3H, s), 6.97 (1H, d, J=8.8 Hz), 7.19(1H, d, J=16.6 Hz), 7.21 (2H, d, J=8.3 Hz), 7.42 (1H, d, J=16.6 Hz),7.57 (2H, d, J=8.3 Hz), 8.04 (1H, dd, J=8.8 Hz, 2.1 Hz), 8.34 (1H, d,J=2.1 Hz).

ESI (LC/MS positive mode) m/z 339 (M+H⁺); retention time 3.88 min(Condition 1 for high-performance liquid chromatography).

Step C: Production ofN-cyclopentyl-4-methoxy-3-[(E)-2-(4-trifluoromethoxy-phenyl)vinyl]benzamide(Compound 2-2-1)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and cyclopentylamine in accordance with thesame procedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 1.52-1.72 (4H, m), 1.72-1.88 (2H, m),1.98-2.11 (2H, m), 3.95 (3H, s), 4.25-4.40 (1H, m), 7.06 (1H, d, J=8.6Hz), 7.26 (2H, d, J=8.9 Hz), 7.28 (1H, d, J=16.9 Hz), 7.49 (1H, d,J=16.9 Hz), 7.64 (2H, d, J=8.9 Hz), 7.77 (1H, dd, J=8.6 Hz, 2.3 Hz),8.13 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 406 (M+H⁺); retention time 3.89 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-2 Production of4-methoxy-N-methyl-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-2)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and methylamine hydrochloride in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 2.92 (3H, s), 3.96 (3H, s), 7.08 (1H, d, J=8.9Hz), 7.26 (2H, d, J=8.5 Hz), 7.26 (1H, d, J=16.8 Hz), 7.49 (1H, d,J=16.8 Hz), 7.63 (2H, d, J=8.5 Hz), 7.76 (1H, dd, J=8.9 Hz, 2.3 Hz),8.12 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 352 (M+H⁺); retention time 3.40 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-3 Production ofN-ethyl-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]benzamide(Compound 2-2-3)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid andethylamine hydrochloride in accordance with the same procedure as in themethods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 1.24 (3H, t, J=7.2 Hz), 3.42 (2H, q, J=7.2Hz), 3.96 (3H, s), 7.07 (1H, d, J=8.6 Hz), 7.26 (2H, d, J=8.6 Hz), 7.27(1H, d, J=16.5 Hz), 7.49 (1H, d, J=16.5 Hz), 7.64 (2H, d, J=8.6 Hz),7.77 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.13 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 366 (M+H⁺); retention time 3.55 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-4 Production ofN-cyclopropyl-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-4)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and cyclopropylamine in accordance with thesame procedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 0.59-0.70 (2H, m), 0.76-0.89 (2H, m),2.78-2.90 (1H, m), 3.95 (3H, s), 7.06 (1H, d, J=8.6 Hz), 7.25 (2H, d,J=9.0 Hz), 7.26 (1H, d, J=16.5 Hz), 7.48 (1H, d, J=16.5 Hz), 7.64 (2H,d, J=9.0 Hz), 7.76 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.11 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 378 (M+H⁺); retention time 3.55 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-5 Production of4-methoxy-N-(1-methoxymethyl-propyl)-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-5)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 2-amino-1-methoxybutane in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 1.48-1.80 (2H, m), 3.38 (3H, s), 3.40-3.56(2H, m), 3.96 (3H, s), 4.10-4.25 (1H, m), 7.08 (1H, d, J=8.8 Hz), 7.26(2H, d, J=8.5 Hz), 7.28 (1H, d, J=16.9 Hz), 7.49 (1H, d, J=16.9 Hz),7.64 (2H, d, J=8.5 Hz), 7.79 (1H, dd, J=8.8 Hz, 2.3 Hz), 8.15 (1H, d,J=2.3 Hz).

ESI (LC/MS positive mode) m/z 424 (M+H⁺); retention time 3.72 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-6 Production ofN-[2-(2-hydroxyethoxy)-ethyl]-4-methoxy-3-[(E)-2-(4-chlorophenyl)-vinyl]-benzamide(Compound 2-2-6)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 2-(2-aminoethoxy)-ethanol in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 426 (M+H⁺); retention time 3.09 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-7 Production of3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzamide (Compound 2-2-7)

Step A: Preparation of ethyl3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoate

The captioned compound was synthesized from diethyl(4-chlorobenzyl)phosphonate and ethyl 3-formyl-4-methoxybenzoateobtained in step C of Example 1-2-1 in accordance with the sameprocedure as in the methods described in step A of Example 2-2-1.

¹H-NMR (400 MHz, CDCl₃) δ 1.41 (3H, t, J=7.2 Hz), 3.98 (3H, s), 4.38(2H, q, J=7.2 Hz), 6.92 (1H, d, J=8.8 Hz), 7.15 (1H, d, J=16.4 Hz), 7.32(2H, d, J=8.8 Hz), 7.41 (1H, d, J=16.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.95(1H, dd, J=8.8 Hz, 2.4 Hz), 8.26 (1H, d, J=2.4 Hz).

Step B: Preparation of 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoicacid

The captioned compound was synthesized using methyl3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoate obtained in step A inaccordance with the same procedure as in the manufacturing methoddescribed in step B of Example 2-2-1.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.94 (3H, s), 7.15 (1H, d, J=8.8 Hz), 7.30(1H, d, J=16.6 Hz), 7.43 (2H, d, J=8.4 Hz), 7.43 (1H, d, J=16.6 Hz),7.64 (2H, d, J=8.4 Hz), 7.88 (1H, dd, J=8.8 Hz, 2.1 Hz), 8.20 (1H, d,J=2.1 Hz), 12.8 (s, 1H).

ESI (LC/MS positive mode) m/z 289, 291 (M+H⁺); retention time 4.00 min(Condition 1 for high-performance liquid chromatography).

Step C: Preparation of3-[(E)-2-(4-chlorophenyl)-vinyl]-4-methoxy-benzamide

The captioned compound was synthesized from3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid obtained in stepB in accordance with the same procedure as in the manufacturing methoddescribed in step G of Example 1-2-1.

¹H-NMR (400 MHz, CDCl₃) δ 3.92 (3H, s), 7.10 (1H, d, J=8.8 Hz), 7.30(1H, d, J=16.2 Hz), 7.43 (2H, d, J=8.6 Hz), 7.43 (1H, d, J=16.2 Hz),7.61 (2H, d, J=8.6 Hz), 7.83 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.93 (1H, brs),8.21 (1H, d, J=2.0 Hz).

ESI (LC/MS positive mode) m/z 288, 290 (M+H⁺); retention time 3.48 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-8 Production of3-[(E)-2-(4-chlorophenyl)-vinyl]-4-methoxy-N-methyl-benzamide (Compound2-2-8)

The captioned compound was synthesized from3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and methylaminehydrochloride in accordance with the same procedure as in themanufacturing method described in step G of Example 1-2-1.

¹H-NMR (270 MHz, CDCl₃) δ 3.02 (3H, d, J=4.6 Hz), 3.92 (3H, s), 6.16(1H, bs), 6.90 (1H, d, J=8.6 Hz), 7.12 (1H, d, J=16.1 Hz), 7.32 (2H, d,J=8.6 Hz), 7.40 (1H, d, J=16.1 Hz), 7.45 (2H, d, J=8.6 Hz), 7.65 (1H,dd, J=8.6 Hz, 2.3 Hz), 8.01 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 302 (M+H⁺); retention time 3.31 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-9 Production of3-[(E)-2-(4-chlorophenyl)-vinyl]-N-ethyl-4-methoxy-benzamide (Compound2-2-9)

The captioned compound was synthesized from3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and ethylaminehydrochloride in accordance with the same procedure as in themanufacturing method described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 1.14 (3H, t, J=7.2 Hz), 3.30 (2H, dq, J=7.2Hz, 6.9 Hz), 3.91 (3H, s), 7.11 (1H, d, J=8.6 Hz), 7.27 (1H, d, J=16.5Hz), 7.43 (1H, d, J=8.6 Hz), 7.44 (1H, d, J=16.5 Hz), 7.44 (2H, d, J=8.6Hz), 7.62 (2H, d, J=8.6 Hz), 7.80 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.16 (1H,d, J=2.3 Hz), 8.42 (1H, bt, J=5.3 Hz).

ESI (LC/MS positive mode) m/z 316, 318 (M+H⁺); retention time 3.81 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-10 Production of3-[(E)-2-(4-chlorophenyl)-vinyl]-N-cyclopentyl-4-methoxy-benzamide(Compound 2-2-10)

The captioned compound was synthesized from3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid andcyclopentylamine in accordance with the same procedure as in themanufacturing method described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 1.42-1.61 (4H, m), 1.61-1.80 (2H, m),1.80-1.95 (2H, m), 3.91 (3H, s), 4.21-4.26 (1H, m), 7.10 (1H, d, J=8.8Hz), 7.28 (1H, d, J=16.5 Hz), 7.43 (2H, d, J=8.5 Hz), 7.43 (1H, d,J=16.5 Hz), 7.63 (2H, d, J=8.5 Hz), 7.81 (1H, dd, J=8.8 Hz, 2.0 Hz),8.14 (1H, d, J=2.0 Hz), 8.21 (1H, bd, J=7.2 Hz).

ESI (LC/MS positive mode) m/z 356, 358 (M+H⁺); retention time 4.20 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-11 Production of3-[(E)-2-(4-chlorophenyl)-vinyl]-N-cyclopropyl-4-methoxy-benzamide(Compound 2-2-11)

The captioned compound was synthesized from3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid andcyclopropylamine in accordance with the same procedure as in themanufacturing method described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 0.50-0.62 (2H, m), 0.62-0.78 (2H, m),2.74-2.92 (1H, m), 3.91 (3H, s), 7.10 (1H, d, J=8.7 Hz), 7.25 (1H, d,J=16.5 Hz), 7.43 (1H, d, J=16.5 Hz), 7.44 (2H, d, J=8.6 Hz), 7.62 (2H,d, J=8.6 Hz), 7.78 (1H, dd, J=8.7 Hz, 2.2 Hz), 8.12 (1H, d, J=2.2 Hz),8.37 (1H, bd, J=4.0 Hz).

ESI (LC/MS positive mode) m/z 328, 330 (M+H⁺); retention time 3.82 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-12 Production of3-[(E)-2-(4-chlorophenyl)-vinyl]-4-methoxy-N-(1-methoxymethyl-propyl)-benzamide(Compound 2-2-12)

The captioned compound was synthesized from3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and2-amino-1-methoxybutane in accordance with the same procedure as in themanufacturing method described in step C of Example 1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 0.98 (3H, t, J=6.6 Hz), 1.48-1.80 (2H, m),3.37 (3H, s), 3.40-3.56 (2H, m), 3.94 (3H, s), 4.11-4.25 (1H, m), 7.05(1H, d, J=8.6 Hz), 7.22 (1H, d, J=16.7 Hz), 7.33 (2H, d, J=8.5 Hz), 7.46(1H, d, J=16.7 Hz), 7.51 (2H, d, J=8.5 Hz), 7.78 (1H, dd, J=8.6 Hz, 2.3Hz), 8.13 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 374, 376 (M+H⁺); retention time 4.02 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-13 Production of3-[(E)-2-(4-chlorophenyl)-vinyl]-N-[2-(2-hydroxyethoxy)-ethyl]-4-methoxy-benzamide(Compound 2-2-13)

The captioned compound was synthesized from3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and2-(2-aminoethoxy)-ethanol in accordance with the same procedure as inthe manufacturing method described in step C of Example 1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 3.54-3.73 (8H, m), 3.95 (3H, s), 7.06 (1H, d,J=8.8 Hz), 7.23 (1H, d, J=16.8 Hz), 7.34 (2H, d, J=8.2 Hz), 7.46 (1H, d,J=16.8 Hz), 7.53 (2H, d, J=8.2 Hz), 7.78 (1H, dd, J=8.8 Hz, 2.1 Hz),8.13 (1H, d, J=2.1 Hz).

ESI (LC/MS positive mode) m/z 376, 378 (M+H⁺); retention time 3.37 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-14 Production of4-bromo-3-[(E)-2-(4-chlorophenyl)-vinyl]-benzamide (Compound 2-2-14)

Step A: Preparation of methyl4-bromo-3-[(E)-2-(4-chlorophenyl)-vinyl]-benzoate

The captioned compound was synthesized from diethyl4-chlorobenzylphosphonate and methyl 3-formyl-4-bromobenzoate inaccordance with the same procedure as in the manufacturing methoddescribed in step A of Example 2-2-1.

ESI (LC/MS positive mode) m/z 351, 353 (M+H⁺); retention time 4.77 min(Condition 1 for high-performance liquid chromatography).

Step B: Preparation of 4-bromo-3-[(E)-2-(4-chlorophenyl)-vinyl]-benzoicacid

The captioned compound was synthesized from methyl4-bromo-3-[(E)-2-(4-chlorophenyl)-vinyl]-benzoate obtained in step A inaccordance with the same procedure as in the manufacturing methoddescribed in step B of Example 2-2-1.

¹H-NMR (270 MHz, DMSO-d₆) δ 7.37 (1H, d, J=16.2 Hz), 7.45 (1H, d, J=16.2Hz), 7.48 (2H, d, J=8.6 Hz), 7.72 (2H, d, J=8.6 Hz), 7.76-7.84 (2H, m),8.32 (1H, d, J=2.0 Hz), 13.32 (1H, bs).

Step C: Preparation of4-bromo-3-[(E)-2-(4-chlorophenyl)-vinyl]-benzamide (Compound 2-2-14)

The captioned compound was synthesized from4-bromo-3-[(E)-2-(4-chlorophenyl)-vinyl]-benzoic acid obtained in step Bin accordance with the same procedure as in the manufacturing methoddescribed in step C of Example 2-2-1.

¹H-NMR (400 MHz, CD₃OD) δ 7.26 (1H, d, J=16.1 Hz), 7.39 (2H, d, J=8.8Hz), 7.50 (1H, d, J=16.1 Hz), 7.59 (2H, d, J=8.8 Hz), 7.65 (1H, dd,J=8.3 Hz, 1.9 Hz), 7.72 (1H, d, J=8.3 Hz), 8.27 (1H, d, J=1.9 Hz).

ESI (LC/MS positive mode) 336, 338 (M+H⁺); retention time 3.78 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-15 Production of3-[(E)-2-(4-chlorophenyl)-vinyl]-4-cyanobenzamide (Compound 2-2-15)

The captioned compound was synthesized from4-bromo-3-[(E)-2-(4-chlorophenyl)-vinyl]-benzamide obtained in Example2-2-14 in accordance with the same procedure as in the manufacturingmethod described in step D of Example 1-1-1.

¹H-NMR (270 MHz, DMSO-d₆) δ 7.42 (1H, d, J=16.4 Hz), 7.52 (2H, d, J=8.4Hz), 7.64 (1H, d, J=16.4 Hz), 7.71 (2H, d, J=8.4 Hz), 7.76 (1H, bs),7.89 (1H, dd, J=8.3 Hz, 1.3 Hz), 7.97 (1H, d, J=8.3 Hz), 8.28 (1H, bs),8.45 (1H, d, J=1.3 Hz).

ESI (LC/MS positive mode) 324, 326 (M+H⁺); retention time 3.44 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-16 Production of4-methoxy-N-[1,2,4]triazol-4-yl-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]benzamide(Compound 2-2-16)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 4-amino-1,2,4-triazole in accordance withthe same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 405 (M+H⁺); retention time 2.75 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-17 Production of4-methoxy-N-pyrrolidin-1-yl-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]benzamide(Compound 2-2-17)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 1-aminopyrrolidine hydrochloride inaccordance with the same procedure as in the methods described in step Cof Example 1-2-3.

ESI (LC/MS positive mode) m/z 407 (M+H⁺); retention time 2.44 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-18 Production of4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]benzoic acidN′-benzylhydrazide (Compound 2-2-18)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and benzylhydrazine hydrochloride inaccordance with the same procedure as in the methods described in step Cof Example 1-2-3.

ESI (LC/MS positive mode) m/z 443 (M+H⁺); retention time 3.57 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-19 Production of4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]benzoic acidN′-(2,2,2-trifluoroethyl)hydrazide (Compound 2-2-19)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 2,2,2-trifluoroethylhydrazine inaccordance with the same procedure as in the methods described in step Cof Example 1-2-3.

ESI (LC/MS positive mode) m/z 435 (M+H⁺); retention time 3.57 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-20 Production of4-methoxy-N-pyridin-4-ylmethyl-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-20)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 4-(aminomethyl)pyridine in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 429 (M+H⁺); retention time 2.67 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-21 Production ofN-(2-cyanoethyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-21)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 3-aminopropionitrile in accordance withthe same procedure as in the methods described in step C of Example1-2-3.

¹H-NMR (270 MHz, CDCl₃) δ 2.70 (2H, t, J=6.0 Hz), 3.66 (2H, q, J=6.0Hz), 3.87 (3H, s), 6.86 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=16.5 Hz), 7.13(2H, d, J=8.9 Hz), 7.33 (1H, d, J=16.5 Hz), 7.47 (2H, d, J=8.9 Hz), 7.60(1H, dd, J=8.6 Hz, 2.3 Hz), 7.97 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 391 (M+H⁺); retention time 3.42 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-22 Production of4-methoxy-N-(2-methoxyethyl)-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-22)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 2-methoxyethylamine in accordance withthe same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 396 (M+H⁺); retention time 3.45 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-23 Production ofN-(2-hydroxyethyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-23)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 2-aminoethanol in accordance with thesame procedure as in the methods described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 382 (M+H⁺); retention time 3.08 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-24 Production ofN-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and tris(hydroxymethyl)aminomethane inaccordance with the same procedure as in the methods described in step Cof Example 1-2-3.

ESI (LC/MS positive mode) m/z 442 (M+H⁺); retention time 3.37 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-25 Production ofN-(2,3-dihydroxy-propyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-25)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 3-amino-1,2-propanediol in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.20-3.30 (1H, m), 3.30-3.50 (3H, m),3.60-3.75 (1H, m), 3.92 (3H, s), 4.61 (1H, t, J=5.6 Hz), 4.85 (1H, d,J=4.6 Hz), 7.13 (1H, d, J=8.5 Hz), 7.30-7.50 (4H, m), 7.72 (2H, d, J=8.9Hz), 7.82 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.21 (1H, d, J=2.0 Hz), 8.41 (1H,bs).

ESI (LC/MS positive mode) m/z 412 (M+H⁺); retention time 3.33 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-26 Production ofN-(2-hydroxy-1-hydroxymethyl-ethyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-26)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and 2-amino-1,3-propanediol in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 412 (M+H⁺); retention time 3.29 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-27 Production ofN-(2-hydroxy-1-methyl-ethyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-27)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and (±)-2-amino-1-propanol in accordance withthe same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 396 (M+H⁺); retention time 3.21 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-28 Production ofN-{2-[2-(2)-hydroxy-ethoxy)-ethoxy]-ethyl}-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-28)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acidobtained in step B of Example 2-2-1 and2-[2-(2-hydroxyethoxy)ethoxy]ethylamine in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 470 (M+H⁺); retention time 3.43 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-29 Production ofN-(1-hydroxymethyl-cyclopropylmethoxy)-4-methoxy-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide(Compound 2-2-29)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acidobtained in step B of Example 2-2-1 andO-(3-hydroxy-2-cyclopropylidene)propyl-hydroxylamine in accordance withthe same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 438 (M+H⁺); retention time 3.64 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-30 Production of3-[(E)-2-(2-fluorophenyl)-vinyl]-4-methoxybenzamide (Compound 2-2-30)

Step A: Preparation of ethyl3-[2-(2-fluorophenyl)-vinyl]-4-methoxybenzoate

N,N-Dimethylformamide (5 mL) was added to 1.0 g of polymer-supportedtriphenylphosphine (produced by Fluka, CAS registry number 39319-11-4)and 1.1 g of 2-fluorobenzyl bromide, and the mixture was stirred for 10hours at 80° C. The reaction mixture was filtered, and then washed withN,N-dimethylformamide, dichloromethane, and methanol. The residue wasdried under reduced pressure to prepare polymer-supported(2-fluorobenzyl)-triphenylphosphonium bromide. This product (144 mg) wasadded to a methanol solution (2 mL) of 30 mg of ethyl3-formyl-4-methoxybenzoate obtained in step C of Example 1-2-1. After 80μL of 28% sodium methoxide was added, the reactor was sealed, and themixture was stirred for 4 hours at 70° C. The residue was diluted withethyl acetate, washed with purified water, and dried over anhydroussodium sulfate. The anhydrous sodium sulfate was separated byfiltration, and then the filtrate was concentrated under reducedpressure. The residue was dried under reduced pressure to obtain 33 mg(80%) of ethyl 3-[2-(2-fluorophenyl)-vinyl]-4-methoxybenzoate.

ESI (LC/MS positive mode) m/z 287 (M+H⁺); retention time 3.67 min(Condition 1 for high-performance liquid chromatography).

Step B: Preparation of3-[(E)-2-(2-fluorophenyl)-vinyl]-4-methoxybenzamide

Ethyl 3-[2-(2-fluorophenyl)-vinyl]-4-methoxybenzoate (30 mg) obtained instep A was dissolved in 3 mL of carbon tetrachloride. Iodine (3 mg) wasadded to the solution, and the mixture was stirred for 7 days at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with a saturated aqueous solution of sodium disulfite, and thenwith a saturated aqueous solution of sodium chloride, and dried overanhydrous sodium sulfate. The anhydrous sodium sulfate was separated byfiltration, and the filtrate was concentrated under reduced pressure.The residue was dissolved in 2 mL of methanol, 100 μL of a 20% aqueoussolution of potassium hydroxide was added to the solution, and themixture was stirred for 3 hours at 60° C. To the reaction mixture, 0.1Mhydrochloric acid was added little by little until the mixture becamenearly pH 2. Then, the mixture was diluted with ethyl acetate, washedwith purified water and a saturated aqueous solution of sodium chloride,and dried over anhydrous sodium sulfate. The anhydrous sodium sulfatewas separated by filtration, and the filtrate was concentrated underreduced pressure. The residue was dissolved in 5 mL ofN,N-dimethylformamide, and 11 mg of ammonium chloride, 24 mg ofbenzotriazol-1-ol monohydrate, 30 mg of(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride, and 54 μL ofN,N-diisopropylethylamine were added to the solution. The resultingsolution was stirred for 15 hours at room temperature, and then 5 mL of0.1M hydrochloric acid was added. This mixture was extracted with ethylacetate twice, whereafter the organic layer combined was washed with asaturated aqueous solution of sodium chloride, and dried over anhydroussodium sulfate. The residue was washed with ethanol, and then driedunder reduced pressure to obtain 14 mg (51%) of3-[(E)-2-(2-fluorophenyl)-vinyl]-4-methoxybenzamide.

ESI (LC/MS positive mode) m/z 272 (M+H⁺); retention time 2.84 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-31 Production ofN-(2,4-dihydroxybutyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide(Compound 2-2-31)

4-Methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]benzoic acid (814mg) obtained in step B of Example 2-2-1 was dissolved in 9 μL ofN,N-dimethylformamide and 10 mL of dichloromethane. Oxalyl chloride(0.32 mL) was added little by little to the solution, and the mixturewas stirred for 4 hours at room temperature. The reaction mixture wasdistilled under reduced pressure, and dried to obtain 850 mg of a lightyellow solid. This solid (200 mg) and 100 mg of 4-amino-3-hydroxybutyricacid were dissolved in 2 mL of N,N-dimethylformamide.N,N-Diisopropylethylamine (293 μL) was added to this solution, and themixture was stirred overnight at room temperature. The reaction mixturewas purified by preparative high-performance liquid chromatography toobtain 55 mg (22%) of3-hydroxy-4-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}butyricacid.

The obtained3-hydroxy-4-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}butyricacid (27 mg) and 15 μL of N-methylmorpholine were dissolved in 3 mL oftetrahydrofuran under an atmosphere of nitrogen, and the solution wascooled to −15° C. Ethyl chloroformate (13 μL) was added to the solution,the mixture was stirred for 15 minutes, and then 18.4 mg of lithiumboron hydride was added. After the mixture was stirred for 30 minutes at−15° C., 1 mL of water was added, and the reaction was quenched. Thereaction mixture was purified by preparative high-performance liquidchromatography to obtain 21 mg (78%) ofN-(2,4-dihydroxybutyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.40-1.51 (1H, m), 1.56-1.68 (1H, m),3.19-3.40 (4H, m), 3.45-3.60 (2H, m), 3.70-3.80 (1H, m), 3.92 (3H, s),7.12 (1H, d, J=8.6 Hz), 7.33 (1H, d, J=16.6 Hz), 7.37 (2H, d, J=8.5 Hz),7.45 (1H, d, J=16.6 Hz), 7.72 (2H, d, J=8.5 Hz), 7.83 (1H, dd, J=8.6 Hz,2.1 Hz), 8.20 (1H, d, J=2.1 Hz), 8.36 (1H, bt, J=5.1 Hz).

ESI (LC/MS positive mode) 426 (M+H⁺); retention time 3.27 min (Condition1 for high-performance liquid chromatography).

Example 2-2-32 Production of4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-N-((2S,3S)-2,3,4-trihydroxy-butyl)benzamide(Compound 2-2-32)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acidobtained in step B of Example 2-2-1 and (2S,3S)-4-amino-1,2,3-butantriol(CAS registry number: 168113-19-7) in accordance with the same procedureas in the methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.24-3.35 (1H, m), 3.38-3.47 (4H, m),3.67-3.72 (1H, m), 3.91 (3H, s), 4.42-4.46 (2H, m), 4.54 (1H, d, J=5.9Hz), 7.11 (1H, d, J=8.8 Hz), 7.30-7.37 (3H, m), 7.43 (1H, d, J=16.6 Hz),7.71 (2H, d, J=8.8 Hz), 7.82 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.19 (1H, d,J=2.4 Hz), 8.39 (1H, t, J=5.9 Hz).

ESI (LC/MS positive mode) m/z 442 (M+H⁺); retention time 2.35 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-33 Production ofN-(2,3-dihydroxy-propyl)-4-methoxy-3-[(E)-2-(4-chlorophenyl)-vinyl]benzamide(Compound 2-2-33)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-7 and 3-amino-1,2-propanediol in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.18-3.24 (1H, m), 3.30-3.44 (3H, m),3.62-3.67 (1H, m), 3.91 (3H, s), 4.58 (1H, t, J=5.9 Hz), 4.83 (1H, d,J=4.9 Hz), 7.11 (1H, d, J=8.8 Hz), 7.29 (1H, d, J=16.6 Hz), 7.41-7.45(3H, m), 7.61 (2H, d, J=8.8 Hz), 7.82 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.19(1H, d, J=2.0 Hz), 8.38 (1H, t, J=5.6 Hz).

ESI (LC/MS positive mode) m/z 362, 364 (M+H⁺); retention time 3.10 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-34 Production ofN-(2-hydroxy-1-hydroxymethyl-ethyl)-4-methoxy-3-[(E)-2-(4-chlorophenyl)-vinyl]benzamide(Compound 2-2-34)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-7 and 2-amino-1,3-propanediol in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.54 (4H, t, J=5.9 Hz), 3.92 (3H, s), 3.98(1H, dt, J=8.1 Hz, 5.9 Hz), 4.66 (2H, t, J=5.9 Hz), 7.11 (1H, d, J=8.8Hz), 7.29 (1H, d, J=16.6 Hz), 7.41-7.45 (3H, m), 7.62 (2H, d, J=8.3 Hz),7.83 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.91 (1H, d, J=8.1 Hz), 8.17 (1H, d,J=2.0 Hz).

ESI (LC/MS positive mode) m/z 362, 364 (M+H⁺); retention time 3.07 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-35 Production ofN-(2-hydroxyethyl)-4-methoxy-3-[(E)-2-(4-chlorophenyl)-vinyl]benzamide(Compound 2-2-35)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-7 and 2-aminoethanol in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.31-3.37 (2H, m), 3.53 (2H, dt, J=6.3 Hz,5.8 Hz), 3.91 (3H, s), 4.74 (1H, t, J=5.8 Hz), 7.11 (1H, d, J=8.8 Hz),7.29 (1H, d, J=16.3 Hz), 7.41-7.45 (3H, m), 7.61 (2H, d, J=8.6 Hz), 7.82(1H, dd, J=8.8 Hz, 2.4 Hz), 8.18 (1H, d, J=2.4 Hz), 8.39 (1H, t, J=5.4Hz).

ESI (LC/MS positive mode) m/z 332, 334 (M+H⁺); retention time 3.25 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-36 Production ofN-(2-hydroxyethyl-1-methyl-ethyl)-4-methoxy-3-[(E)-2-(4-chlorophenyl)-vinyl]benzamide(Compound 2-2-36)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-7 and (±)-2-amino-1-propanol in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 346, 348 (M+H⁺); retention time 3.36 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-37 Production of3-[(E)-2-(4-chlorophenyl)-vinyl]-4-methoxy-N-((2S,3S)-2,3,4-trihydroxy-butyl)benzamide(Compound 2-2-37)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-7 and (2S,3S)-4-amino-1,2,3-butanetriol (CAS registrynumber: 168113-19-7) in accordance with the same procedure as in themethods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.24-3.29 (1H, m), 3.38-3.47 (4H, m),3.67-3.71 (1H, m), 3.90 (3H, s), 4.41-4.46 (2H, m), 4.53 (1H, d, J=5.4Hz), 7.11 (1H, d, J=8.8 Hz), 7.28 (1H, d, J=16.6 Hz), 7.40-7.45 (3H, m),7.61 (2H, d, J=8.8 Hz), 7.81 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.18 (1H, d,J=2.0 Hz), 8.37 (1H, t, J=5.6 Hz).

ESI (LC/MS positive mode) m/z 392, 394 (M+H⁺); retention time 2.11 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-38 Production ofN-(2,3-dihydroxy-propyl)-4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzamide(Compound 2-2-38)

Step A: Preparation of4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid

The captioned compound was synthesized from ethyl4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]-benzoate, which hadbeen synthesized from diethyl (4-trifluoromethylbenzyl)phosphonate andethyl 3-formyl-4-methoxybenzoate obtained in step C of Example 1-2-1, inaccordance with the same procedure as in the methods described in step Bof Example 2-2-1.

¹H-NMR (270 MHz, CD₃OD) δ 3.99 (3H, s), 7.10 (1H, d, J=8.6 Hz), 7.28(1H, d, J=16.5 Hz), 7.60 (1H, d, J=16.5 Hz), 7.64 (2H, d, J=8.6 Hz),7.73 (2H, d, J=8.8 Hz), 7.98 (1H, dd, J=2.3 Hz, 8.6 Hz), 8.30 (1H, d,J=2.3 Hz). EI-MS (positive mode) m/z 322 (M⁺).

Step B: Preparation ofN-(2,3-dihydroxy-propyl)-4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzamide

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtainedin step A of Example 2-2-38 and 3-amino-1,2-propanediol in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 3.43 (1H, dd, J=6.9 Hz, 13.9 Hz), 3.51-3.63(3H, m), 3.80-3.89 (1H, m), 3.97 (3H, s), 7.10 (1H, d, J=8.9 Hz), 7.33(1H, d, J=16.5 Hz), 7.62 (1H, d, J=16.5 Hz), 7.64 (2H, d, J=8.6 Hz),7.73 (2H, d, J=8.6 Hz), 7.82 (1H, dd, J=2.0 Hz, 8.9 Hz), 8.19 (1H, d,J=2.0 Hz).

ESI (LC/MS positive mode) m/z 396 (M+H⁺); retention time 2.87 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-39 Production ofN-(2-hydroxy-1-hydroxymethyl-ethyl)-4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzamide(Compound 2-2-39)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtainedin step A of Example 2-2-38 and 2-amino-1,3-propanediol in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

¹H-NMR (270 MHz, CD₃OD) δ 3.75 (4H, d, J=5.6 Hz), 3.93 (3H, s), 4.19(1H, quint., J=5.6 Hz), 7.09 (1H, d, J=8.6 Hz), 7.34 (1H, d, J=16.5 Hz),7.57-7.66 (3H, m), 7.72 (2H, d, J=8.6 Hz), 7.84 (1H, dd, J=2.3 Hz, 8.6Hz), 8.21 (1H, d, J=2.3 Hz).

ESI (LC/MS positive mode) m/z 396 (M+H⁺); retention time 2.84 min(Condition 3 for high-performance liquid chromatography).

Example 2-2-40 Production ofN-(2-hydroxyethyl)-4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)-vinyl]benzamide(Compound 2-2-40)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-38 and 2-aminoethanol in accordance with thesame procedure as in the methods described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 366 (M+H⁺); retention time 2.58 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-41 Production ofN-(2-hydroxy-1-methylethyl)-4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)-vinyl]benzamide(Compound 2-2-41)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-38 and (±)-2-amino-1-propanol in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 380 (M+H⁺); retention time 2.73 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-42 Production ofN-[2-(2-hydroxyethoxy)-ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)-vinyl]benzamide(Compound 2-2-42)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-38 and 2-(2-aminoethoxy)ethanol in accordancewith the same procedure as in the methods described in step C of Example1-2-3.

ESI (LC/MS positive mode) m/z 410 (M+H⁺); retention time 2.59 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-43 Production ofN-(2,3-dihydroxypropyl)-4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]-4-benzamide(Compound 2-2-43)

Step A: Preparation of ethyl3-(E)-2-(4-bromophenyl)vinyl]-4-methoxybenzoate

The captioned compound was synthesized from diethyl(4-bromobenzyl)phosphonate and ethyl 3-formyl-4-methoxybenzoate obtainedin step C of Example 1-2-1 in accordance with the same procedure as inthe methods described in step A of Example 2-2-1.

¹H-NMR (400 MHz, CDCl₃) δ 1.41 (3H, t, J=7.3 Hz), 3.95 (3H, s), 4.38(2H, q, J=7.3 Hz), 6.92 (1H, d, J=8.6 Hz), 7.13 (1H, d, J=16.6 Hz), 7.41(2H, d, J=8.5 Hz), 7.42 (1H, d, J=16.6 Hz), 7.48 (2H, d, J=8.5 Hz), 7.96(1H, dd, J=8.6 Hz, 2.1 Hz), 8.26 (1H, d, J=2.1 Hz).

ESI (LC/MS positive mode) 361, 363 (M+H⁺); retention time 4.12 min(Condition 2 for high-performance liquid chromatography).

Step B: Preparation of 3-[(E)-2-(4-bromophenyl)vinyl]-4-methoxybenzoicacid

The captioned compound was synthesized from ethyl3-[(E)-2-(4-bromophenyl)vinyl]-4-methoxybenzoate obtained in step A inaccordance with the same procedure as in the methods described in step Bof Example 2-2-1.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.94 (3H, s), 7.15 (1H, d, J=8.6 Hz), 7.29(1H, d, J=16.6 Hz), 7.44 (1H, d, J=16.6 Hz), 7.56 (2H, d, J=9.8 Hz),7.58 (2H, d, J=9.8 Hz), 7.88 (1H, dd, J=8.6 Hz, 2.0 Hz), 8.21 (1H, d,J=2.1 Hz), 12.75 (1H, bs).

ESI (LC/MS positive mode) 333, 335 (M+H⁺); retention time 3.15 min(Condition 1 for high-performance liquid chromatography).

Step C: Preparation ofN-(2,3-dihydroxypropyl)-4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]-4-benzamide

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-43 and 3-amino-1,2-propanediol in accordance with thesame procedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.17-3.24 (1H, m), 3.35 (2H, t, J=5.9 Hz),3.38-3.44 (1H, m), 3.61-3.68 (1H, m), 3.92 (3H, s), 4.57 (1H, t, J=5.9Hz), 4.82 (1H, d, J=4.9 Hz), 7.12 (1H, d, J=8.8 Hz), 7.28 (1H, d, J=16.4Hz), 7.45 (1H, d, J=16.4 Hz), 7.55 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8Hz), 7.82 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.19 (1H, d, J=2.0 Hz), 8.38 (1H,t, J=5.9 Hz).

ESI (LC/MS positive mode) 406, 408 (M+H⁺); retention time 3.17 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-44 Production of3-[(E)-2-(4-bromophenyl)vinyl]-N-(2-hydroxy-1-hydroxymethylethyl)-4-methoxybenzamide(Compound 2-2-44)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-43 and 2-amino-1,3-propanediol in accordance with thesame procedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.54 (4H, t, J=5.9 Hz), 3.92 (3H, s),3.94-4.02 (1H, m), 4.66 (2H, t, J=5.9 Hz), 7.12 (1H, d, J=8.8 Hz), 7.28(1H, d, J=16.1 Hz), 7.45 (1H, d, J=16.1 Hz), 7.55 (2H, d, J=9.5 Hz),7.58 (2H, d, J=9.5 Hz), 7.83 (1H, dd, J=8.8 Hz, 2.1 Hz), 7.92 (1H, d,J=7.8 Hz), 8.18 (1H, d, J=2.1 Hz).

ESI (LC/MS positive mode) 406, 408 (M+H⁺); retention time 3.14 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-45 Production of3-[(E)-2-(4-bromophenyl)-vinyl]-N-(2-hydroxyethyl)-4-methoxybenzamide(Compound 2-2-45)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-43 and 2-aminoethanol in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 376, 378 (M+H⁺); retention time 2.52 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-46 Production of3-[(E)-2-(4-bromophenyl)-vinyl]-N-(2-hydroxy-1-methylethyl)-4-methoxybenzamide(Compound 2-2-46)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-38 and (±)-2-amino-1-propanol in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 390, 392 (M+H⁺); retention time 2.70 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-47 Production of3-[(E)-2-(4-bromophenyl)-vinyl]-N-[2-(2-hydroxyethoxy)-ethyl]-4-methoxybenzamide(Compound 2-2-47)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-38 and 2-(2-aminoethoxy)ethanol in accordance with thesame procedure as in the methods described in step C of Example 1-2-3.

ESI (LC/MS positive mode) m/z 420, 422 (M+H⁺); retention time 2.53 min(Condition 2 for high-performance liquid chromatography).

Example 2-2-48 Production ofN—[(R)-2,3-dihydroxy-propyl)]-4-methoxy-3-[(E)-2-(4-chlorophenyl)-vinyl]benzamide(Compound 2-2-48)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-7 and (R)-(+)-3-amino-1,2-propanediol (produced by WakoPure Chemical Industries) in accordance with the same procedure as inthe methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.18-3.24 (1H, m), 3.30-3.44 (3H, m),3.62-3.67 (1H, m), 3.91 (3H, s), 4.58 (1H, t, J=5.9 Hz), 4.83 (1H, d,J=4.9 Hz), 7.11 (1H, d, J=8.8 Hz), 7.29 (1H, d, J=16.6 Hz), 7.41-7.45(3H, m), 7.61 (2H, d, J=8.8 Hz), 7.82 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.19(1H, d, J=2.0 Hz), 8.38 (1H, t, J=5.6 Hz).

ESI (LC/MS positive mode) m/z 362, 364 (M+H⁺); retention time 3.10 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-49 Production ofN—[(S)-2,3-dihydroxy-propyl)]-4-methoxy-3-[(E)-2-(4-chlorophenyl)-vinyl]benzamide(Compound 2-2-49)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step Bof Example 2-2-7 and (S)-(−)-3-amino-1,2-propanediol (produced by WakoPure Chemical Industries) in accordance with the same procedure as inthe methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.18-3.24 (1H, m), 3.30-3.44 (3H, m),3.62-3.67 (1H, m), 3.91 (3H, s), 4.58 (1H, t, J=5.9 Hz), 4.83 (1H, d,J=4.9 Hz), 7.11 (1H, d, J=8.8 Hz), 7.29 (1H, d, J=16.6 Hz), 7.41-7.45(3H, m), 7.61 (2H, d, J=8.8 Hz), 7.82 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.19(1H, d, J=2.0 Hz), 8.38 (1H, t, J=5.6 Hz).

ESI (LC/MS positive mode) m/z 362, 364 (M+H⁺); retention time 3.10 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-50 Production of(R)—N-(2,3-dihydroxy-propyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-50)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acidobtained in step B of Example 2-2-1 and (R)-3-amino-1,2-propanediol(produced by Wako Pure Chemical Industries) in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.20-3.30 (1H, m), 3.30-3.50 (3H, m),3.60-3.75 (1H, m), 3.92 (3H, s), 4.61 (1H, t, J=5.6 Hz), 4.85 (1H, d,J=4.6 Hz), 7.13 (1H, d, J=8.5 Hz), 7.30-7.50 (4H, m), 7.72 (2H, d, J=8.9Hz), 7.82 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.21 (1H, d, J=2.0 Hz), 8.41 (1H,bs).

ESI (LC/MS positive mode) m/z 412 (M+H⁺); retention time 3.33 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-51 Production of(S)—N-(2,3-dihydroxy-propyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)-vinyl]-benzamide(Compound 2-2-51)

The captioned compound was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acidobtained in step B of Example 2-2-1 and (S)-3-amino-1,2-propanediol(produced by Wako Pure Chemical Industries) in accordance with the sameprocedure as in the methods described in step C of Example 1-2-3.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.20-3.30 (1H, m), 3.30-3.50 (3H, m),3.60-3.75 (1H, m), 3.92 (3H, s), 4.61 (1H, t, J=5.6 Hz), 4.85 (1H, d,J=4.6 Hz), 7.13 (1H, d, J=8.5 Hz), 7.30-7.50 (4H, m), 7.72 (2H, d, J=8.9Hz), 7.82 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.21 (1H, d, J=2.0 Hz), 8.41 (1H,bs).

ESI (LC/MS positive mode) m/z 412 (M+H⁺); retention time 3.33 min(Condition 1 for high-performance liquid chromatography).

Example 2-2-52 Production ofN—[(S)-2-hydroxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide(Compound 2-2-52)

The(S)-3-t-butoxy-2-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}propionicacid was synthesized from4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtainedin step B of Example 2-2-1 and O-t-butyl-L-serine in accordance with thesame procedure as in the methods described in step C of Example 1-2-3.

(S)-3-t-butoxy-2-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}propionicacid (25 mg), 2-hydroxyethylamine (9 μL), benzotriazol-1-ol monohydrate(19 mg), and (3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (25mg) were dissolved in 2 mL of N,N-dimethylformamide, and then,N,N-diisopropylethyl-amine (53 μL) was added to the solution. Thesolution was stirred overnight at room temperature. Then,2-hydroxyethylamine (9 μL), benzotriazol-1-ol monohydrate (19 mg), and(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (25 mg) wereadded again to the solution, and the solution was further stirredovernight. After removal of the solvent under reduced pressure, to theobtained residue was added water, and the mixture was extracted threetimes with dichloromethane. The respective organic layers were combined,whereafter the combined organic layer was washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous sodiumsulfate. The anhydrous sodium sulfate was separated by filtration, andwashed with dichloromethane. The filtrate and the washings werecombined, and dichloromethane was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography toobtain 44 mg (76%) ofN—[(S)-2-t-butoxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzamide.

Trifluoroacetic acid (1 mL) was added to 20 mg ofN-[(S)-2-t-butoxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzamideand the mixture was stirred for 20 minutes at room temperature. Afterremoval of the solvent, the resulting residue was purified using amicromass spectrometer (ZMD produced by Micromass) equipped with agradient high-performance liquid chromatograph 996-600E produced byWaters. The resulting solid was dried under reduced pressure to obtain 9mg (57%) ofN—[(S)-2-hydroxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide.

ESI (LC/MS positive mode) m/z 469 (M+H⁺); retention time 3.13 min(Condition 1 for high-performance liquid chromatography).

Example 2-3-1 Production of3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxybenzamide (Compound 2-3-1)

Step A: Preparation of ethyl 3-dimethoxymethyl-4-methoxybenzoate

Ethyl 3-formyl-4-methoxybenzoate (500 mg) obtained in step C of Example1-2-1 was dissolved in 10 mL of methanol. Trimethyl orthoformate (263μL) and 41 mg of p-toluenesulfonic acid monohydrate were added to thesolution, and then the mixture was heated for 2 hours under reflux.After the reaction solution was cooled, 5 mL of a saturated aqueoussolution of sodium bicarbonate was added, and the resulting mixture wasconcentrated under reduced pressure. The residue was diluted with ethylacetate, washed with purified water and then with a saturated aqueoussolution of sodium chloride, and dried over anhydrous sodium sulfate.The anhydrous sodium sulfate was separated by filtration, whereafter thefiltrate was concentrated under reduced pressure. The residue was driedunder reduced pressure to obtain 596 mg (97%) of ethyl3-dimethoxymethyl-4-methoxybenzoate.

¹H-NMR (270 MHz, CDCl₃) δ 1.38 (3H, t, J=7.3 Hz), 3.37 (6H, s), 3.91(3H, s), 4.36 (2H, q, J=7.3 Hz), 5.67 (1H, s), 6.93 (1H, d, J=8.6 Hz),8.04 (1H, dd, J=8.6 Hz, 2.3 Hz), 8.21 (1H, d, J=2.3 Hz).

Step B: Preparation of 3-dimethoxymethyl-4-methoxybenzoic acid

Ethyl 3-dimethoxymethyl-4-methoxybenzoate (3.67 g) obtained in step Awas dissolved in 20 mL of methanol, 12 mL of a 20% aqueous solution ofpotassium hydroxide was added to the solution, and the mixture wasstirred for 3 hours at 50° C. The reaction mixture was cooled to 0° C.,and 1M hydrochloric acid was added little by little until the mixturebecame nearly pH 7, whereafter the mixture was concentrated underreduced pressure. The residue was diluted with ethyl acetate, washedwith purified water and then with a saturated aqueous solution of sodiumchloride, and dried over anhydrous sodium sulfate. The anhydrous sodiumsulfate was separated by filtration, and the filtrate was concentratedunder reduced pressure. The residue was dried under reduced pressure toobtain 1.82 g (55%) of 3-dimethoxymethyl-4-methoxybenzoic acid.

¹H-NMR (270 MHz, CDCl₃) δ 3.36 (6H, s), 3.94 (3H, s), 5.68 (1H, s), 6.96(1H, d, J=8.6 Hz), 8.10 (1H, dd, J=8.6 Hz, 2.0 Hz), 8.29 (1H, d, J=2.0Hz).

Step C: Preparation of 3-formyl-4-methoxybenzamide

3-Dimethoxymethyl-4-methoxybenzoic acid (1.81 g) obtained in step B,0.65 g of ammonium chloride, 1.48 g of benzotriazol-1-ol monohydrate,and 1.85 g of (3-dimethylaminopropyl)ethylcarbodiimide hydrochloridewere dissolved in 50 mL of N,N-dimethylformamide, and 4.20 mL ofN,N-diisopropylethylamine was added to the solution. The resultingsolution was stirred for 13 hours at room temperature, and then 1Mhydrochloric acid was added little by little until the mixture reachednearly pH 2. This mixture was extracted with ethyl acetate twice,whereafter the organic layer combined was washed with a saturatedaqueous solution of sodium chloride, and dried over anhydrous sodiumsulfate. The residue was washed with ethanol, and then dried underreduced pressure to obtain 1.03 g (71%) of 3-formyl-4-methoxybenzamide.

¹H-NMR (270 MHz, CDCl₃) δ 4.02 (3H, s), 7.11 (1H, d, J=8.6 Hz),8.18-8.24 (2H, m), 10.48 (1H, s).

Step D: Preparation of3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxybenzamide

N,N-Dimethylformamide (5 mL) was added to 1.0 g of polymer-supportedtriphenylphosphine (produced by Fluka, CAS registry number 39319-11-4)and 1.1 g of 3-fluorobenzyl bromide, and the mixture was stirred for 10hours at 80° C. The reaction mixture was filtered, and then washed withN,N-dimethylformamide, dichloromethane, and methanol. The residue wasdried under reduced pressure to prepare polymer-supported(3-fluorobenzyl)triphenylphosphonium bromide. This product (111 mg) wasadded to a methanol solution (2 mL) of 20 mg of3-formyl-4-methoxybenzamide obtained in step B. After 62 μL of 28%sodium methoxide was added, the reactor was sealed, and the mixture wasstirred for 4 hours at 70° C. The reaction mixture was purified bythin-layer chromatography to obtain 4 mg (13%) of3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxybenzamide.

ESI (LC/MS positive mode) m/z 272 (M+H⁺); retention time 3.29 min(Condition 1 for high-performance liquid chromatography).

Example 2-3-2 Production of4-methoxy-3-[(E)-2-(2,4,6-trifluorophenyl)-vinyl]benzamide (Compound2-3-2)

The captioned compound was synthesized from 2,4,6-trifluorobenzylbromide by the same procedure as in step D of Example 2-3-1.

ESI (LC/MS positive mode) m/z 308 (M+H⁺); retention time 3.33 min(Condition 1 for high-performance liquid chromatography).

Example 2-3-3 Production of3-[(E)-2-(2,3-difluorophenyl)-vinyl]-4-methoxybenzamide (Compound 2-3-3)

The captioned compound was synthesized from 2,3-difluorobenzyl bromideby the same procedure as in step D of Example 2-3-1.

ESI (LC/MS positive mode) m/z 290 (M+H⁺); retention time 3.28 min(Condition 1 for high-performance liquid chromatography).

Example 2-3-4 Production of3-[(E)-2-(3-chloro-2-fluorophenyl)-vinyl]-4-methoxybenzamide (Compound2-3-4)

The captioned compound was synthesized from 3-chloro-2-fluorobenzylbromide by the same procedure as in step D of Example 2-3-1.

ESI (LC/MS positive mode) m/z 306, 308 (M+H⁺); retention time 3.46 min(Condition 1 for high-performance liquid chromatography).

Example 2-3-5 Production of3-[(E)-2-(2-fluoro-4-methylphenyl)-vinyl]-4-methoxybenzamide (Compound2-3-5)

The captioned compound was synthesized from 2-fluoro-4-methylbenzylbromide by the same procedure as in step D of Example 2-3-1.

ESI (LC/MS positive mode) m/z 286 (M+H⁺); retention time 3.41 min(Condition 1 for high-performance liquid chromatography).

Example 2-3-6 Production of4-methoxy-3-[(E)-2-(4-trifluoromethylsulfanil-phenyl)-vinyl]-benzamide(Compound 2-3-6)

A mixture of 4-(trifluoromethylthio)benzyl bromide (50.4 mg) andtriethyl phosphite (32 μL) was stirred for 16 hours at 160° C. After thereaction mixture was cooled to room temperature, 20 mg of3-formyl-4-methoxybenzamide, 26 mg of1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine, and 1 mL oftetrahydrofuran were added, and the mixture was stirred for 24 hours atroom temperature and for 6 hours at 70° C. 3-Formyl-4-methoxybenzamide(20 mg) was further added, and the mixture was stirred for 24 hours at70° C. This mixture was cooled to room temperature, then diluted withmethanol, and passed through an SCX solid phase extraction column (1 g,produced by Varian). The eluate was concentrated to obtain 93 mg of acrude product. This product (46 mg) was purified using a micromassspectrometer (ZMD produced by Micromass) equipped with a gradienthigh-performance liquid chromatograph 996-600E produced by Waters. Theresulting solid was dried under reduced pressure to obtain 3.5 mg (6%)of4-methoxy-3-[(E)-2-(4-trifluoromethylsulfanil-phenyl)-vinyl]-benzamide.

ESI (LC/MS positive mode) m/z 354 (M+H⁺); retention time 3.77 min(Condition 1 for high-performance liquid chromatography).

Example 2-3-7 Production of3-[(E)-2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-benzamide (Compound2-3-7)

The captioned compound was synthesized from2-fluoro-4-trifluoromethylbenzyl bromide and 3-formyl-4-methoxybenzamideby the same procedure as in the manufacturing method described inExample 2-3-6.

ESI (LC/MS positive mode) m/z 340 (M+H⁺); retention time 3.25 min(Condition 3 for high-performance liquid chromatography).

Example 2-3-8 Production of3-[2-(4-cyano-phenyl)-vinyl]-4-methoxy-benzamide (Compound 2-3-8)

The captioned compound was synthesized from 4-cyanobenzyl bromide and3-formyl-4-methoxybenzamide by the same procedure as in themanufacturing method described in Example 2-3-6.

ESI (LC/MS positive mode) m/z 279 (M+H⁺); retention time 2.86 min forZ-form, 2.98 min for E-form (Condition 1 for high-performance liquidchromatography).

Example 2-4-1 Production of3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxybenzamide (Compound 2-4-1)

Step A: Preparation of 3-(diethoxyphosphonylmethyl)-4-methoxy-benzoicacid

Ethyl 3-chloromethyl-4-methoxy-benzoate (10.00 g) obtained in step A ofExample 1-2-1 was dissolved in 8.25 mL of triethyl phosphite, and thesolution was stirred for 24 hours at 160° C. After cooling, the reactionmixture was dissolved in 200 mL of methanol, 36 mL of a 20% aqueoussolution of potassium hydroxide was added to the solution, and themixture was stirred for 1 hour at 60° C. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withpurified water, and washed with diethyl ether. With the addition of 1Mhydrochloric acid, the aqueous layer was brought to nearly pH 2, andthen extracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, and dried over anhydroussodium sulfate. The anhydrous sodium sulfate was separated byfiltration, and the filtrate was concentrated under reduced pressure.The residue was dried under reduced pressure to obtain 12.78 g (98%) of3-(diethoxyphosphonylmethyl)-4-methoxy-benzoic acid.

¹H-NMR (270 MHz, DMSO-d₆) δ 1.16 (6H, t, J=7.3 Hz), 3.22 (2H, d, J=21.4Hz), 3.87 (3H, s), 3.94 (4H, quintet, J=7.3 Hz), 7.09 (1H, d, J=8.3 Hz),7.82-7.87 (2H, m), 12.62 (1H, bs).

Step B: Preparation of Polymer-Supported3-(diethoxyphosphonylmethyl)-4-methoxy-benzamide

A solvent mixture (1:4) (50 mL) of piperidine and N,N-dimethylformamidewas added to 8.06 g of Rink resin (produced by Advanced Chemtech, 0.8mmol/g), and the mixture was vigorously agitated for 3 hours at roomtemperature. After the reaction mixture was filtered, the remainingresin was washed with dichloromethane and methanol, and dried underreduced pressure (results of Kaiser test: positive). To this resin,there were added 50 mL of N-methyl-2-pyrrolidinone, 5.85 g of3-(diethoxyphosphonylmethyl)-4-methoxy-benzoic acid obtained in step A,4.94 g of benzotriazol-1-ol monohydrate, and 4.99 mL ofN,N-diisopropylcarbodiimide hydrochloride, and the mixture was stirredfor 15 hours at room temperature. The reaction mixture was filtered, andwashed with dichloromethane and methanol. The residue was dried underreduced pressure to prepare polymer-supported3-(diethoxyphosphonylmethyl)-4-methoxy-benzamide. Results of Kaisertest: Negative.

Step C: Preparation of3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxybenzamide

The resin (100 mg) obtained in step B was transferred into a reactor,where 54 μL of 4-fluorobenzaldehyde, 70 mg of1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine, and 1.5 mL ofN,N-dimethylformamide were added, and the mixture was stirred for 13hours at 80° C. The reaction mixture was filtered, and then washed withmethanol and dichloromethane. To the remaining resin, 2 mL of a 20%dichloromethane solution of trifluoroacetic acid was added, and themixture was vigorously agitated for 30 seconds. The reaction mixture wasfiltered, and then washed with dichloromethane, followed byconcentrating the filtrate under reduced pressure. The residue waspurified using a micromass spectrometer (ZMD produced by Micromass)equipped with a gradient high-performance liquid chromatograph 996-600Eproduced by Waters. The resulting solid was dried under reduced pressureto obtain 6 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxybenzamide.

ESI (LC/MS positive mode) m/z 272 (M+H⁺); retention time 2.39 min(Condition 2 for high-performance liquid chromatography).

Example 2-4-2 Production of 4-methoxy-3-((E)-2-p-toluyl-vinyl)-benzamide(Compound 2-4-2)

The captioned compound was synthesized from 4-methylbenzaldehyde by thesame procedure as in step C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 268 (M+H⁺); retention time 2.59 min(Condition 2 for high-performance liquid chromatography).

Example 2-4-3 Production of3-[(E)-2-(4-ethylphenyl)-vinyl)-4-methoxy-benzamide (Compound 2-4-3)

The captioned compound was synthesized from 4-ethylbenzaldehyde by thesame procedure as in step C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 282 (M+H⁺); retention time 2.88 min(Condition 2 for high-performance liquid chromatography).

Example 2-4-4 Production of4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)-vinyl)-benzamide (Compound2-4-4)

The captioned compound was synthesized from4-trifluoromethylbenzaldehyde by the same procedure as in step C ofExample 2-4-1.

ESI (LC/MS positive mode) m/z 322 (M+H⁺); retention time 2.86 min(Condition 2 for high-performance liquid chromatography).

Example 2-4-5 Production of3-[(E)-2-(4-tert-butylphenl)-vinyl]-4-methoxybenzamide (Compound 2-4-5)

The captioned compound was synthesized from 4-(tert-butyl)benzaldehydeby the same procedure as in step C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 310 (M+H⁺); retention time 3.26 min(Condition 2 for high-performance liquid chromatography).

Example 2-4-6 Production of3-((E)-2-biphenyl-4-yl-vinyl]-4-methoxybenzamide (Compound 2-4-6)

The captioned compound was synthesized from biphenyl-4-carbaldehyde bythe same procedure as in step C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 330 (M+H⁺); retention time 3.13 min(Condition 2 for high-performance liquid chromatography).

Example 2-4-7 Production of3-[(E)-2-(4-bromophenyl)-vinyl]-4-methoxybenzamide (Compound 2-4-7)

The captioned compound was synthesized from 4-bromobenzaldehyde by thesame procedure as in step C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 332, 334 (M+H⁺); retention time 2.79 min(Condition 2 for high-performance liquid chromatography).

Example 2-4-8 Production of3-[(E)-2-(4-bromo-2-fluorophenyl)-vinyl]-4-methoxybenzamide (Compound2-4-8)

The captioned compound was synthesized from 4-bromo-2-fluorobenzaldehydeby the same procedure as in step C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 350, 352 (M+H⁺); retention time 3.56 min(Condition 1 for high-performance liquid chromatography).

Example 2-4-9 Production of3-[(E)-2-(2,4-dichlorophenyl)-vinyl]-4-methoxybenzamide (Compound 2-4-9)

The captioned compound was synthesized from 2,4-dichlorobenzaldehyde bythe same procedure as in step C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 322, 324 (M+H⁺); retention time 3.59 min(Condition 1 for high-performance liquid chromatography).

Example 2-4-10 Production of3-{(E)-2-[4-(4-fluorobenzyloxy)-3-methoxyphenyl]-vinyl}-4-methoxybenzamide(Compound 2-4-10)

The captioned compound was synthesized from4-(4-fluorobenzyloxy)-3-methoxybenzaldehyde by the same procedure as instep C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 408 (M+H⁺); retention time 3.54 min(Condition 1 for high-performance liquid chromatography).

Example 2-4-11 Production of3-[(E)-2-(2,4-fluorophenyl)-vinyl]-4-methoxybenzamide (Compound 2-4-11)

The captioned compound was synthesized from 2,4-difluorobenzaldehyde bythe same procedure as in step C of Example 2-4-1.

ESI (LC/MS positive mode) m/z 290 (M+H⁺); retention time 3.27 min(Condition 1 for high-performance liquid chromatography).

Example 2-4-12 Production of4-methoxy-3-((E)-2-pyridin-3-yl-vinyl)benzamide (Compound 2-4-12)

Step A: Preparation of 3-(diethoxyphosphonylmethyl)-4-methoxy-benzamide

3-(Diethoxyphosphonylmethyl)-4-methoxy-benzoic acid (3.00 g) obtained instep A of Example 2-4-1, 1.06 g of ammonium chloride, 2.28 g ofbenzotriazol-1-ol monohydrate, and 2.85 g of(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride were dissolved in90 mL of N,N-dimethylformamide, and 5.18 mL of N,N-diisopropylethylaminewas added. This solution was stirred for 12 hours at room temperature,and then concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to obtain 2.78 g (92%) of3-(diethoxyphosphonylmethyl)-4-methoxy-benzamide.

¹H-NMR (270 MHz, DMSO-d₆) δ 1.16 (6H, t, J=6.9 Hz), 3.18 (2H, d, J=21.5Hz), 3.85 (3H, s), 3.93 (4H, quintet, J=6.9 Hz), 7.3 (1H, d, J=9.2 Hz),7.19 (1H, bs), 7.78-7.85 (3H, m).

Step B: Preparation of 4-methoxy-3-((E)-2-pyridin-3-yl-vinyl)benzamide

3-(Diethoxyphosphonylmethyl)-4-methoxy-benzamide (30 mg) obtained instep A, 28 μL of pyridine-3-carbaldehyde, 40 mg of1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine, and 1.0 mL ofN,N-dimethylformamide were added, and the mixture was stirred for 12hours at 80° C. The reaction mixture was filtered, and then the filtratewas purified using a micromass spectrometer (ZMD produced by Micromass)equipped with a gradient high-performance liquid chromatograph 996-600Eproduced by Waters. The resulting solid was dried under reduced pressureto obtain 6 mg (24%) of 4-methoxy-3-((E)-2-pyridin-3-yl-vinyl)benzamide.

¹H-NMR (270 MHz, DMSO-d₆) δ 3.93 (3H, s), 7.12 (1H, d, J=8.8 Hz), 7.28(1H, bs), 7.33 (1H, d, J=17.0 Hz), 7.41 (1H, dd, J=8.4 Hz, 4.4 Hz), 7.52(1H, d, J=17.0 Hz), 7.85 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.94 (1H, bs),8.03-8.06 (1H, m), 8.23 (1H, d, J=2.4 Hz), 8.47 (1H, dd, 4.4 Hz, 1.6Hz), 8.75 (1H, d, J=2.4 Hz).

ESI (LC/MS positive mode) m/z 255 (M+H⁺); retention time 1.78 min(Condition 1 for high-performance liquid chromatography).

Example 2-5-1 Production of4-bromo-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide (Compound2-5-1)

Diethyl (4-trifluoromethoxybenzyl)phosphonate (7.8 g) was dissolved in100 mL of DMF, 5.0 g of 4-bromo-3-formyl-benzonitrile was added, and themixture was cooled to −25° C. Potassium tert-butoxide (6.4 g) was added,and the mixture was stirred for 2 hours at −25° C. To the reactionmixture, 100 mL of a saturated aqueous solution of ammonium chloride and100 mL of water were added, and the mixture was extracted 3 times withethyl acetate (100 mL). The respective organic layers were combined,whereafter the combined organic layer was washed with water and asaturated aqueous solution of sodium chloride, and dried over magnesiumsulfate. The magnesium sulfate was separated by filtration, and thefiltrate was concentrated under reduced pressure. The residue wassubjected to 100 g silica gel column chromatography to obtain 3.9 g of4-bromo-3-[2-(4-trifluoromethoxy-phenyl)-vinyl]-benzonitrile as a crudeproduct with the use of an eluant (ethyl acetate and n-hexane, 1:10).

The crude product was dissolved in 100 mL of carbon tetrachloride, 0.4 gof iodine was added, and the mixture was stirred for 15.5 hours at roomtemperature under irradiation with a 500 W halogen lamp. A solution of2.7 g of sodium dithionite dissolved in 157 mL of water was added to thereaction mixture for washing, and the organic layer was washed with asaturated aqueous solution of sodium chloride, and dried over magnesiumsulfate. The magnesium sulfate was separated by filtration, and then thefiltrate was concentrated under reduced pressure to obtain 3.8 g ofyellow crystals.

The crystals were dissolved in 35 mL of dimethyl sulfoxide, and asolution of 2.8 g of potassium carbonate dissolved in 5.2 mL of a 30%aqueous solution of hydrogen peroxide was slowly added at 0° C.,followed by stirring the mixture for 1.5 hours at room temperature.Water was added to the reaction suspension, and the resultingprecipitate was filtered, washed with water, and dried under reducedpressure to obtain crude crystals of4-bromo-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide. Theresulting crude crystals were recrystallized from methanol to obtain 1.1g of 4-bromo-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide.

¹H-NMR (400 MHz, CDCl₃) δ 8.15 (1H, d, J=2.4 Hz), 7.68 (1H, d, J=8.3Hz), 7.58 (2H, d, J=8.3 Hz), 7.50 (1H, dd, J=8.3 Hz, 2.4 Hz), 7.48 (1H,d, J=16.1 Hz), 7.24 (1H, d, J=8.3 Hz), 7.13 (1H, d, J=16.1 Hz).

ESI (LC/MS positive mode) m/z 386, 388 (M+H⁺); retention time 3.20 min(Condition 2 for high-performance liquid chromatography).

Example 2-5-2 Production of4-(2-hydroxy-ethylamino)-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide(Compound 2-5-2)

The interior of a container containing4-bromo-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide (50.2 mg)obtained in Example 2-5-1, 2.8 mg of tris(dibenzylideneacetone)dipalladium(0), 10 μL of ethanolamine, and 2.6 mg of2-(dicyclohexylphosphino)biphenyl was purged with argon. A 1.0Mtetrahydrofuran solution (1 mL) of lithium bis(trimethylsilyl)amide wasadded into the container, and the mixture was stirred for 3.5 hours at65° C. Then, 2.0 mg of tris(dibenzylideneacetone) dipalladium(0), and 10μL of ethanolamine were further added, the interior of the container waspurged with argon, and the mixture was stirred for 13.5 hours at 65° C.The reaction mixture was cooled to room temperature, and 2 mL of 1Nhydrochloric acid was added for neutralization, followed by extractingthe aqueous layer with ethyl acetate 4 times. After the respectiveorganic layers were combined, the combined organic layer was filteredthrough Presep Dehydration Column (produced by Wako Pure ChemicalIndustries), and the filtrate was concentrated under reduced pressure.The resulting residue was subjected to 11 g silica gel columnchromatography to obtain 5.6 mg of4-(2-hydroxy-ethylamino)-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamidewith the use of an eluant (dichloromethane and methanol, 15:1).

¹H-NMR (400 MHz, CD₃OD) δ 7.91 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=8.8Hz, 2.4 Hz), 7.60 (1H, d, J=8.8 Hz), 7.27 (1H, d, J=16.1 Hz), 7.16 (1H,d, J=8.8 Hz), 7.02 (1H, d, J=16.1 Hz), 6.64 (1H, d, J=8.8 Hz), 3.69 (2H,t, J=5.9 Hz), 3.30 (2H, t, J=5.9 Hz).

ESI (LC/MS positive mode) m/z 367 (M+H⁺); retention time 2.96 min(Condition 1 for high-performance liquid chromatography).

Example 2-5-3 Production of4-pyrrolidin-1-yl-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide(Compound 2-5-3)

The captioned compound was synthesized from4-bromo-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide andpyrrolidine by the same procedure as in Example 2-5-2.

ESI (LC/MS positive mode) m/z 407 (M+H⁺); retention time 3.09 min(Condition 1 for high-performance liquid chromatography).

Example B-1 Cell Proliferation Assay

The test compound was serially diluted with DMSO, and then diluted 1:50with a Ca²⁺,Mg²⁺-free phosphate-buffered physiological saline. Theresulting dilution (10 μl) was dispensed into a 96-well plate. Humanumbilical vein endothelial cells (HUVEC, purchased from Clonetics) weresuspended in PRMI 1640 medium supplemented with 10% bovine fetal serum,30 μg/mL vascular endothelial cell growth supplement, and 50 μg/mLheparin. Human lung carcinoma cell line Calu-6 was suspended in MEMmedium supplemented with 10% bovine fetal serum, 0.1 mM nonessentialamino acid, and 1 mM sodium pyruvate. Each cell suspension (190 μL) wasdispensed into the plate containing the test compound such that the cellcount per well was 3,000 cells. The plate was incubated in a CO₂incubator (37° C., 5% CO₂). After 72 hours, 20 μL WST-1 (produced byRoche Diagnostics) was added to each well and, after 2 hours ofincubation, the absorbance at 450 nm (reference wavelength: 650 nm) wasmeasured. The 50% growth inhibition concentration (IC₅₀ value) of thetest compound was calculated from the inhibition rate obtained when thetest compound was added, in comparison with the reference value obtainedwhen the test compound was not added.

The IC₅₀ values, for HUVEC and Calu-6, of representative examples of thecompounds of the present invention are shown in Table 1.

TABLE 1 50% growth inhibition concentration (IC₅₀ value)/μM CompoundHUVEC Calu-6 1-1-1 2.27 >100 1-2-1 2.40 >100 1-3-1 0.19 >50 1-3-20.15 >50 1-3-5 0.14 >50 1-3-6 0.24 >50 1-3-7 0.28 >50 1-3-8 0.35 >501-3-10 0.76 >50 1-3-12 2.54 >50 1-3-16 4.60 >50 1-3-17 1.20 >25 1-3-181.25 >50 1-3-21 5.10 >50 1-3-23 2.85 >50 1-3-24 5.19 >50 1-3-39 2.36 >251-3-41 0.04 >50 1-3-45 0.05 >50 2-1-1 0.17 >100 2-2-1 3.35 >50 2-2-22.27 >50 2-2-9 1.41 >25

As described in Table 1, the compounds of the present invention havemore potent cell growth inhibiting activity against human umbilical veinendothelial cells (HUVEC) than against human lung carcinoma cell lineCalu-6.

Example B-2 Tube Formation Assay

An angiogenesis measurement kit (produced by KURABO) was charged withthe test compound at final concentration of 20 μM, and incubated in aCO₂ incubator (37° C., 5%). After 11 days of incubation, capillary-liketubes formed were fixed with 70% ethanol and visualized with a CD31staining kit (produced by KURABO). Under a microscope, stain images ofthe wells were photographed, stored as an image file, and measured forthe area of capillary-like tube formation by use of angiogenesisquantitative determination software of KURABO. The inhibition rates (%)of the test compound-charged wells were calculated, with the controltaken as 100%.

The capillary-like tube formation inhibiting rates at 20 μM, againstHUVEC, of representative examples of the compounds of the presentinvention are shown in Table 2.

TABLE 2 Capillary-like tube formation inhibiting activity Capillary-liketube formation Compound inhibition rates (%) 1-1-1 43 1-2-1 68 1-3-5 911-3-6 46 1-3-7 67 1-3-10 46 1-3-12 27 1-3-16 80 1-3-17 80 1-3-18 291-3-21 71 1-3-23 27 1-3-24 28 1-3-39 20 1-3-41 82 1-3-45 31 2-1-1 932-2-1 60 2-2-2 77 2-2-9 79

As described above, the compounds concerned with the present inventioninhibit the capillary-like tube formation of human-originated vascularendothelial cells.

Example B-3 Antitumor Test

A cell suspension of human lung carcinoma cell line Calu-6 was preparedusing Hanks' balanced salt solution, and 5.0×10⁶ of the cells wereimplanted subcutaneously in the flank region of female Balb/c nude mice.When the volume of the tumor reached 200 to 250 mm³, the test compoundwas orally administered once daily for 11 days. The tumor volume wascalculated from the equation π/6×(long diameter×shortdiameter×thickness). The tumor growth inhibition rate was calculatedfrom changes in the tumor volume in the test compound treatment grouprelative to changes in the tumor volume in the control group.

The results of the antitumor test of compound 1-1-1 and compound 2-1-1,as representative examples of the compounds of the present invention,are shown in FIGS. 1-(A) and 1-(B) and 2-(A) and 2-(B). As shown inFIGS. 1-(A) and 2-(A), the compounds according to the present inventionhad antitumor activity, and the tumor growth inhibition rates (TGI) bytreatment with 600 mg/kg of compound 1-1-1 and compound 2-1-1 were 82%and 75%, respectively. As shown in FIG. 1-B and FIG. 2-B, moreover, nodecreases in the body weights of the mice were observed, and no findingsof toxicity observed, following treatment with the test compounds.

Example B-4 Measurement of the Number of Blood Vessels in the Tumor

5.0×10⁶ Cells of human lung carcinoma cell line Calu-6 were implantedsubcutaneously in the flank region of female Balb/c nude mice. When thevolume of tumor reached 200 to 250 mm³, the test compound was orallyadministered once daily for 11 days. Twenty-four hours after the finaladministration, xenograft tissue was removed from the mice, and a middleportion of the long diameter of the tumor was embedded, as a block 2 to3 mm thick, in O.C.T. Compound, and preserved as a frozen tissuespecimen. Frozen sections were prepared, and blood vessels in the tumortissue were stained by an immunohistological method using anti-mouseCD31 antibody. The stained tissue was photographed under a microscope,and the images were stored as an image file. The number of the stainedblood vessels was measured by Image Pro (Promega). The decrease rate ofblood vessel density was calculated as a decrease rate relative to theblood vessel density in the control group.

The decrease rates of the blood vessel density in the tumor tissuefollowing treatment with 600 mg/kg of compound 1-1-1 and compound 2-1-1,as representative examples of the compounds of the present invention,are shown in Table 3.

TABLE 3 Decrease rate of blood vessel density in tumor tissue Decrease(%) in intratumor Compound blood vessel density 1-1-1 44 2-1-1 37

As described above, the compounds according to the present inventionhave in vivo anti-angiogenic activity.

1. A compound of formula (II) or a pharmaceutically acceptable saltthereof:

where A₁ is C—X₁; Q₁ is -A₂=A₃-; Q₂ is -A₄=A₅-; A₂ is C—X₂, A₃ is C—X₃,A₄ is C—X₄, and A₅ is C—X₅; X₁, X₂, X₃, X₄ and X₅ are each independentlyselected from the group consisting of a hydrogen atom, hydroxy, ahalogen atom, cyano, hydroxyaminocarbonyl, hydroxyamidino, nitro, amino,amidino, guanidino, C₁₋₆alkylamino, diC₁₋₆alkylamino, C₁₋₆alkylamidino,diC₁₋₆alkylamidino, C₁₋₆alkylguanidino, diC₁₋₆alkylguanidino,C₁₋₆alkylthio, C₁₋₆alkylsulfo, C₁₋₆alkylsulfonyl, C₁₋₆alkylphosphono,diC₁₋₆alkylphosphono, C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₉ cycloalkyl,C₃₋₉cycloalkoxy, C₂₋₇alkenyl, C₂₋₇alkynyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl (the immediately preceding 19 groups may besubstituted by one or more substituents selected from a halogen atom,hydroxy, aryl, heteroaryl, and cyano), aryl, aryloxy, arylcarbonyl,heteroaryl, heteroaryloxy, heteroarylcarbonyl, and arylC₁₋₆alkyloxy (theimmediately preceding 7 groups may be substituted by one or moresubstituents selected from a halogen atom, C₁₋₆alkyl, and C₁₋₆alkoxy);or X₁ and X₂, X₂ and X₃, X₃ and X₄, and X₄ and X₅, together with thecarbon atoms to which they are bound, form a saturated or unsaturated 5-to 7-membered carbocyclic ring, or a saturated or unsaturated 5- to7-membered heterocyclic ring containing one or more heteroatoms selectedfrom an oxygen atom, a nitrogen atom, and a sulfur atom; Y is selectedfrom the group consisting of C₃₋₉cycloalkyl, C₂₋₇alkenyl, C₂₋₇alkynyl,C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, C₁₋₆alkoxy, C₂₋₇alkenyloxy,C₂₋₇alkynyloxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl {the immediatelypreceding 14 groups may be substituted by one or more substituentsselected from a saturated or unsaturated 3- to 7-membered carbocyclyl, asaturated or unsaturated 3- to 7-membered heterocyclyl containing one ormore heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom, a halogen atom, hydroxy, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy, N—C₁₋₆alkylaminoC₁₋₆alkoxy,N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino, C₁₋₆alkylamino,hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino, aminoC₁₋₆alkylamino,diC₁₋₆alkylamino, bis(hydroxyC₁₋₆alkyl)amino,bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆alkyl)amino, amidino,C₁₋₆alkylamidino, diC₁₋₆alkylamidino, guanidino, C₁₋₆alkylguanidino,diC₁₋₆alkylguanidino, cyano, carboxyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkylphosphono, anddiC₁₋₆alkylphosphono}, amino, C₁₋₆alkylamino, diC₁₋₆alkylamino (theimmediately preceding 2 groups may be substituted by one or moresubstituents selected from a saturated or unsaturated 3- to 7-memberedcarbocyclyl, a saturated or unsaturated 3- to 7-membered heterocyclylcontaining one or more heteroatoms selected from an oxygen atom, anitrogen atom, and a sulfur atom, a halogen atom, hydroxy, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy,N—C₁₋₆alkylaminoC₁₋₆alkoxy, N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino,C₁₋₆alkylamino, hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, diC₁₋₆alkylamino, bis(hydroxyC₁₋₆alkyl)amino,bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆alkyl) amino, amidino,C₁₋₆alkylamidino, diC₁₋₆alkylamidino, guanidino, C₁₋₆alkylguanidino,diC₁₋₆alkylguanidino, cyano, carboxyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkylphosphono, anddiC₁₋₆alkylphosphono), a halogen atom, nitro, cyano, carboxyl, and asaturated or unsaturated 3- to 7-membered heterocyclyl containing one ormore heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom (the heterocyclyl may be substituted by one or moresubstituents selected from hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, and oxo); Z is selected from thegroup consisting of a hydrogen atom, hydroxy, C₁₋₆alkyl, C₃₋₉cycloalkyl{the immediately preceding 2 groups may be substituted by one or moresubstituents selected from a saturated or unsaturated 3- to 7-memberedcarbocyclyl (the carbocyclyl group may be substituted by one or moresubstituents selected from C₁₋₆alkyl, hydroxyC₁₋₆alkyl, andC₁₋₆alkoxyC₁₋₆alkyl), a saturated or unsaturated 3- to 7-memberedheterocyclyl containing one or more heteroatoms selected from an oxygenatom, a nitrogen atom, and a sulfur atom (the heterocyclyl group may besubstituted by one or more substituents selected from C₁₋₆alkyl,hydroxyC₁₋₆alkyl, and C₁₋₆alkoxyC₁₋₆alkyl), a halogen atom, hydroxy,C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy,hydroxyC₁₋₆alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy,N—C₁₋₆alkylaminoC₁₋₆alkoxy, N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino,C₁₋₆alkylamino, hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, diC₁₋₆alkylamino, bis(hydroxyC₁₋₆alkyl) amino,bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆alkyl)amino, cyano,carboxyl, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, carbamoyl,C₁₋₆alkylcarbamoyl, diC₁₋₆alkylcarbamoyl (the immediately preceding 2groups may be substituted by one or more substituents selected from ahalogen atom, hydroxy, cyano and amino), phosphono, C₁₋₆alkylphosphono,diC₁₋₆alkylphosphono, sulfonic acid, and C₁₋₆alkylsulfo}, and —OR₁ and—NR₁R₂; R₁ and R₂ are each dependently selected from the groupconsisting of a hydrogen atom, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, and asaturated or unsaturated 3- to 7-membered heterocyclyl containing one ormore heteroatoms selected from an oxygen atom, a nitrogen atom, and asulfur atom (the immediately preceding 3 groups may be substituted byone or more substituents selected from a saturated or unsaturated 3- to7-membered carbocyclyl, a saturated or unsaturated 3- to 7-memberedheterocyclyl containing one or more heteroatoms selected from an oxygenatom, a nitrogen atom, and a sulfur atom, a halogen atom, hydroxy,C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, aminoC₁₋₆alkoxy,N—C₁₋₆alkylaminoC₁₋₆alkoxy, N,N-diC₁₋₆alkylaminoC₁₋₆alkoxy, amino,C₁₋₆alkylamino, hydroxyC₁₋₆alkylamino, C₁₋₆alkoxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, diC₁₋₆alkylamino, bis(hydroxyC₁₋₆alkyl) amino,bis(C₁₋₆alkoxyC₁₋₆alkyl)amino, bis(aminoC₁₋₆alkyl)amino, cyano,carboxyl, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, phosphono,C₁₋₆alkylphosphono, diC₁₋₆alkylphosphono, sulfonic acid, andC₁₋₆alkylsulfo); or R₁ and R₂, together with the nitrogen atoms to whichthey are bound, form a saturated or unsaturated 5- to 7-memberedheterocyclic ring containing one nitrogen atom and optionally furthercontaining one or more heteroatoms selected from an oxygen atom, anitrogen atom, and a sulfur atom; and L is:


2. The compound or the pharmaceutically acceptable salt thereofaccording to claim 1, wherein Z is a hydrogen atom, C₁₋₆alkyl,C₃₋₉cycloalkyl, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, pyridylC₁₋₆alkyl,dihydroxyC₁₋₆alkyl, trihydroxyC₁₋₆alkyl, morpholinoC₁₋₆alkyl,(N,N-diC₁₋₆alkylamino)C₁₋₆alkyl, or (N,N-bis(hydroxyC₁₋₆alkyl) amino)C₁₋₆alkyl.
 3. The compound or the pharmaceutically acceptable saltthereof according to claim 2, wherein Z is a hydrogen atom, methyl,ethyl, cyclopropyl, cyclopentyl, 2-hydroxyethyl,2-(2-hydroxyethoxy)ethyl, 2-methoxyethyl, 2-cyanoethyl, 4-pyridylmethyl,1-methoxybut-2-yl, 2,3-dihydroxyprop-1-yl, 1,3-dihydroxyprop-2-yl,1,3-dihydroxy-2-hydroxymethylprop-2-yl, 2-morpholinoethyl,1-hydroxyprop-2-yl, 1-hydroxy-3-methylbut-2-yl,2-(N,N-dimethylamino)ethyl, 2-(N,N-bis(2-hydroxyethyl)amino)ethyl,2,4-dihydroxylbutyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl,or 2,3,4,5,6-pentahydroxyhexyl.
 4. The compound or the pharmaceuticallyacceptable salt thereof according to claim 1, wherein Y is a halogenatom, cyano, C₂₋₇alkenyl, C₂₋₇alkynyl, C₁₋₆alkoxy,C₃₋₉cycloalkylC₁₋₆alkoxy, C₂₋₇alkynyloxy, or haloC₁₋₆alkoxy.
 5. Thecompound or the pharmaceutically acceptable salt thereof according toclaim 4, wherein Y is chloro, bromo, cyano, ethynyl, methoxy,trifluoromethoxy, cyclopropylmethoxy, 2-butyn-1-yloxy, or2-chloroethoxy.
 6. The compound or the pharmaceutically acceptable saltthereof according to claim 1, wherein X₁, X₂, X₃, X₄ and X₅ are eachindependently selected from a hydrogen atom, a halogen atom, C₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, C₁₋₆alkylthio, andhaloC₁₋₆alkylthio; or X₁ and X₂, X₂ and X₃, X₃ and X₄, and X₄ and X₅,together with the carbon atoms to which they are bound, form acyclohexane ring, a cyclopentane ring, a benzene ring, a pyridine ring,a pyrimidine ring, a 1,4-dioxane ring, a 1,3-dioxolane ring, a pyrrolering, an imidazole ring, a thiazole ring, or a furan ring.
 7. Thecompound or the pharmaceutically acceptable salt thereof according toclaim 6, wherein X₁, X₂, X₃, X₄ and X₅ are each independently selectedfrom a hydrogen atom, fluoro, chloro, bromo, methyl, ethyl, t-butyl,i-propyl, methoxy, i-propoxy, trifluoromethyl, trifluoromethoxy,methylthio, and trifluoromethylthio; or X₁ and X₂, together with thecarbon atoms to which they are bound, form a cyclohexane ring; X₁ andX₂, together with the carbon atoms to which they are bound, form apyridine ring; X₂ and X₃, together with the carbon atoms to which theyare bound, form a 1,4-dioxane ring; or X₂ and X₃, together with thecarbon atoms to which they are bound, form a cyclopentane ring.
 8. Apharmaceutical composition containing the compound, or thepharmaceutically acceptable salt thereof, according to claim 1, as anactive ingredient.